SmI2-promoted cross coupling reaction of N-2-bromoethylphthalimide and carbonyl compounds: Synthesis of α-aryl-α′-hydroxy ketones

Article abstract of DOI:10.1016/j.tet.2019.130839

In this paper, we have disclosed the SmI₂-mediated carbonyl-imide reductive cross coupling between N-2-bromoethylphthalimide and different aldehydes and ketones in the presence of anhydrous catalytic NiI₂. This methodology provided a

Full text of DOI:10.1016/j.tet.2019.130839

Journal Pre-proof
SmI2-promoted cross coupling reaction of N-2-bromoethylphthalimide and carbonyl
compounds: Synthesis of α-aryl-α′-hydroxy ketones
Jorge González-Rodríguez, Martín Soto, Raquel G. Soengas, Humberto Rodríguez-
Solla
PII:
S0040-4020(19)31247-5
https://doi.org/10.1016/j.tet.2019.130839
TET 130839
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 September 2019
Revised Date: 22 November 2019
Accepted Date: 26 November 2019
Please cite this article as: González-Rodríguez J, Soto Martí, Soengas RG, Rodríguez-Solla H, SmI2-
promoted cross coupling reaction of N-2-bromoethylphthalimide and carbonyl compounds: Synthesis of
α-aryl-α′-hydroxy ketones, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130839.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered
SmI2-promoted cross coupling reaction of N-
2-bromoethylphthalimide and carbonyl
compounds: synthesis of α-aryl-α’-hydroxy
ketones
Leave this area blank for abstract info.
Jorge González-Rodríguez, Martín Soto, Raquel G. Soengas, Humberto Rodríguez-Solla
Dept. of Organic and Inorganic Chemistry, University of Oviedo, Julián Clavería 8, 33006, Oviedo (Spain)

3

Tetrahedron
journal homepage: www.elsevier.com
SmI2-promoted cross coupling reaction of N-2-bromoethylphthalimide and carbonyl
compounds: synthesis of α-aryl-α’-hydroxy ketones†
Jorge González-Rodríguez, Martín Soto, Raquel G. Soengas, Humberto Rodríguez-Solla
Department of Organic and Inorganic Chemistry, University of Oviedo, Julián Clavería 8, 33006, Oviedo (Spain)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this paper, we have disclosed the SmI2-mediated carbonyl-imide reductive cross coupling
between N-2-bromoethylphthalimide and different aldehydes and ketones in the presence of
anhydrous catalytic NiI2. This methodology provided an effective tool to prepare α-aryl-α’-
hydroxy ketones under mild conditions which can be applied to various functionalised, aliphatic
and aromatic aldehydes and ketones.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Cross coupling reaction
Samarium diiodide
α-Hydroxy ketones
Pinacol coupling
† Dedicated to Prof. Steve G. Davies as a recognition for his many scientific achievements and for all his time.
1

1. Introduction
Samarium diiodide1 is unique when compared with other
single electron transfer (SET) reagents due to its well-known
versatility in providing different radicals in organic synthesis.2
The use of samarium diiodide in different reductive processes,3
including coupling reactions, has been widely covered in the
literature.4 In this regard, SmI2 has been used to promote cross-
coupling reactions of aldehydes,5 ketones6 and imines7 under mild
conditions. It has been reported that the ketyl-radical generated in
situ after reaction of one equivalent of SmI2 and the
corresponding carbonyl compound affords, after hydrolysis, 1,2-
diols or 1,2-diamines with excellent control of the selectivity.8 In
general, amides exhibit low reactivity in SmI2-mediated cross
coupling reactions,9 however, cyclic imides have been reported to
be much more reactive, undergoing intra- and intermolecular
reactions in the presence of samarium diiodide at room
temperature.10
additives.2c In this regard, Fe(III) and Ni(II) salts are frequently
used as additives in Sm(II)-mediated transformations.30 With the
aim of increasing the selectivity and efficiency of this reaction,
we next investigated the reaction of n-octanal 1a (1.0 equiv.), N-
2-bromoethylphthalimide 2 (1.0 equiv.) and SmI2 (2.0 equiv.) in
the presence of different salts (FeCl3, NaI and NiI2) as additives
(Table 1, entries 2-5).
Table 1. Screening of different additives for the samarium-
promoted synthesis of 3a.
α-Hydroxy ketones are compounds of great biological and
chemical interest. For instance, the α-hydroxy ketone function is
found in several pharmaceutical products such as antidepressants,
anti-dementia drugs,11 farnesyl transferase inhibitors,12 and
antitumorals.13 In addition, α-hydroxy ketones are valuable
building blocks for the synthesis of many other important
structures of pharmacological interest such as amino ketones,14
amino alcohols15 or diols.16 As a consequence, several procedures
have been described for the preparation of these compounds
including the α-oxidation of ketones, enol ethers or enolates,17 the
oxidation of alkenes,18 the metal-catalyzed heteroatom transfer19
and the acyloin condensation of aldehydes.20 However, these
reported methods have several drawbacks, including low yields,
poor chemoselectivities and the generation of toxic waste.
a
Entry
Additive
3a/4ab
Yield (%)c
1
2
3
4
5
-
1/3.7
1/4
15
18
37
75
76
FeCl3 (5 mol%)
NaI (5 mol%)
NiI2 (5 mol%)
NiI2 (1 mol%)
1/1.2
6/1
6/1
a
All reactions were carried out with 1.0 equiv. of n-octanal, 1.0 equiv. of N-2-
bromoethylphthalimide, 2.0 equiv. of SmI2 and the corresponding additive. b 3a/4a
ratio was determined by 1H NMR (300 MHz) analysis of the crude reaction
mixture. c Isolated yield of compound 3a after column chromatography based on
starting aldehyde 1a.
The use of N-bromoethylphthalimide has additional value
since it allows the incorporation of the 2-aryloxazoline moiety
into the final products. Thus, the 2-aryloxazoline scaffold is
present in the structure of many biologically relevant derivatives
which exhibit cytotoxic,21 antibacterial,22 antitumoral,23
antidepressant,24 and antioxidant25 activities. In addition, 2-
aryloxazolines have a wide range of chemical applications,
including: as chiral auxiliaries,26 ligands in catalysis,27 and
synthetic intermediates.28
Table 1 shows that the addition of FeCl3 led to similar results
to those obtained in the absence of any additive (Table 1, entry
2). The use of sodium iodide led to slightly improved results,
affording an almost equimolar mixture of 3a and diol 4a from
which the desired α-hydroxyketone 3a was isolated in 37% yield
(Table 1, entry 3). Finally, it was found that Ni(II) salts
effectively promoted the reaction to afford α-hydroxyketone 3a
(Table 1, entries 4-5). The best results, with regard to both the
yield and chemoselectivity, were obtained when SmI2 (0.1 M in
THF, 2.0 equiv.) and NiI2 (1.0 mol%) were added to a solution of
aldehyde 1a (1.0 equiv.) and N-2-bromoethylphthalimide 2 (1.0
equiv.) in THF and the resulting mixture was stirred at r.t. for 4
h. Under these conditions, α-hydroxyketone 3a was isolated in a
76% yield after flash column chromatography (Table 1, entry 5).
In view of the aforementioned synthetic and pharmacological
importance of α-hydroxy ketone and oxazoline moieties, we
envisioned the SmI2-mediated aldehyde-imide reductive cross-
coupling reaction as an effective tool to prepare these key
intermediates. Thus, in connection with our long term interest in
the study of highly selective and effective SmI2-mediated
processes,29 herein we described a samarium-promoted reductive
cross-coupling reaction of N-bromoethylphthalimide with
different aldehydes and ketones in the presence of catalytic NiI2
allowing access to the oxazoline-derived α-aryl-α’-hydroxy
ketone moiety.
With the optimal conditions in hand, we tested the generality
of this procedure for a variety of aldehydes in which the R group
can be aliphatic (linear, cyclic and branched) 1a-e, unsaturated
1f-g, and aromatic 1h-l. (Table 2). Thus, a mixture of the
2. Results and Discussion
In our preliminary studies, the model reaction of n-octanal 1a
with N-2-bromoethylphthalimide 2 was studied (Table 1). Thus,
corresponding
aldehyde
1a-l
(1.0
equiv.),
N-2-
bromoethylphthalimide 2 (1.0 equiv.), SmI2 (0.1 M in THF, 2.0
equiv.) and NiI2 (1.0 mol%) in THF were stirred at room
temperature for 4 h. As shown in Table 2, when aliphatic
aldehydes 1a-e (Table 2, entries 1-5) were employed, α-aryl-α’-
hydroxy ketones 3a-g were isolated in good yields after flash
column chromatography. No significant differences were
observed when functionalized aldehydes 1f-g were employed,
with the desired compounds 3f-g obtained in moderate to good
yields. In contrast, aromatic aldehydes 1h-l showed moderate or
when
a
mixture of n-octanal 1a (1.0 equiv.), N-2-
bromoethylphthalimide 2 (1.0 equiv.) and SmI2 (2.0 equiv.) in
THF was stirred for 4 h at room temperature, a crude was
obtained, containing 15% of the octanal-derived α-aryl-α’-
hydroxy ketone 3a, along with diol 4a derived from the
homocoupling reaction of n-octanal 1a (Table 1, entry 1).
It is well known that the reactivity of SmI2 can be easily
modulated by a judicious choice of different co-solvents or
2

low reactivity towards the reductive cross-coupling, which is in
accordance with the reported facility of aromatic aldehydes to
undergo SmI2-mediated pinacol homocouplings.31 Thus,
benzaldehyde 1h and other aromatic aldehydes substituted with
electron-donating groups 1i and 1j afforded, in moderate yields,
the desired α-hydroxy ketones 3h-j (Table 2, entries 8-10). On
the other hand, aldehydes containing electron-withdrawing
groups 1k-l afforded α-hydroxy ketone 3k with very poor yield
(Table 2, entry 11) or failed to give the desired cross-coupling
compound 3l (Table 2, entry 12). This behavior for aromatic
aldehydes is also in accordance with results previously published
in the literature. Thus, aromatic aldehydes bearing electron-
withdrawing groups are generally known to facilitate formation
of the pinacol homocoupling compound32 resulting in lower
yields of the cross-coupling adducts. It is noteworthy that this
methodology would complement others previously reported by
Yoda10c and Kise,10h in which the SmI2-mediated pinacol-type
cyclization of N-(γ-keto)phthalimides afforded α-hydroxylactams
and/or 1,2-diols, respectively.
Scheme 1. SmI2-promoted synthesis of ketone-derived α-aryl-
α’-hydroxy ketones 6.
In general terms, no significant differences were observed
when this reaction was carried out using aldehydes 1 or ketones
5.
α-Aryl-α’-hydroxy ketones 3 and 6 were fully characterized
by 1H NMR (300 MHz), 13C NMR (75 MHz), DEPT, HMBC and
HSQC experiments, HRMS and other conventional techniques.
The formation of hydroxyl ketones 3 and 6 could be explained
by assuming two SET reactions. Thus, after two samarium-
promoted monoelectronic transferences to aldehyde 1a and N-2-
bromoethylphthalimide 2, both samarium (III)-bound ketyl
radical species 7 and 8 would be formed, respectively. Cross-
coupling of both, ketyl radical 7 and imide-derived ketyl radical
8, would afford intermediate 9 which then would give the
dianionic species 10. Intramolecular heterocyclization of 10,
followed by hydrolysis of the resulting intermediate 11, would
finally afford α-aryl-α'-hydroxy ketones 3 and 5 (Scheme 1).
Table 2. Synthesis of α-aryl-α'-hydroxy ketones 3.
a
Entry
1
R
3
Yield (%)b
1
2
1a
1b
1c
1d
1e
1f
n-C7H15
n-C5H11
3a
3b
3c
3d
3e
3f
76
77
71
69
65
70
52
40
48
55
10
n.r.
3
c-C6H11
4
i-Pr
5
s-Bu
6
(Z)-EtCH=CH(CH2)5
(E)-PhCH=CH
Ph
7
1g
1h
1i
3g
3h
3i
8
Scheme 2. Proposed mechanism for the formation of 3a.
9
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-MeO2CC6H4
3. Conclusion
10
11
12
1j
3j
In summary, we have herein disclosed the SmI -mediated
2
carbonyl-imide reductive cross-coupling between N-2-
bromoethylphthalimide and both aldehydes and ketones, in the
1k
1l
3k
3l
presence of catalytic NiI , which provided an effective tool to
2
prepare functionalized α-aryl-α’-hydroxy ketones under mild
conditions. Taking into account the potential chemical and
biological interest of α-hydroxy ketones, this procedure may
eventually find application in the synthesis of bioactive products.
Studies directed towards the synthesis of α-amino-α’-aryl ketones
and other related compounds, including the asymmetric version,
are currently under investigation in our laboratory.
a
All reactions were carried out with 1.0 equiv. of aldehyde, 1.0 equiv. of N-2-
bromoethylphthalimide, 2.0 equiv. of SmI2 and 1% mol of NiI2. b Isolated yield of
compounds 3 after flash column chromatography based on aldehydes 1.
In order to increase the scope of this reaction, further studies
were also carried out using ketones (3-pentanone 5a,
cyclopentanone 5b, and cyclohexanone 5c) as starting materials.
Under the conditions reported above, ketones 5a-c reacted with
N-2-bromoethylphthalimide 2 to give the desired α-aryl-α’-
hydroxy ketones 6a-c in moderate yields (Scheme 1).
4. Experimental Section
All reactions were conducted under dry nitrogen atmosphere.
The glassware was oven dried (120 °C). THF was distilled from
sodium/benzophenone ketyl immediately prior to use. All
reagents were purchased in the highest quality available and were
used without further purification. Flash column chromatography
3

was carried out on silica gel 230-400 mesh. Compounds were
visualized on analytical thin layer chromatograms (TLC) by UV
1 H), 3.60-3.53 (m, 1 H), 3.38-3.29 (m, 1 H), 2.92-2.79 (m, 1 H),
1.07 (d, J = 6.6 Hz, 3 H), 0.99 (d, J = 7.0 Hz, 3 H). 13C NMR (75
MHz, CDCl3): δ 208.9 (C), 169.1 (C), 139.0 (C), 132.2 (CH),
131.5 (C), 129.3 (CH), 124.4 (CH), 122.2 (CH), 69.8 (CH), 44.1
(CH2), 36.7 (CH2), 29.8 (CH), 19.3 (CH3), 17.8 (CH3). MS (ESI--
TOF, m/z, %): 246 ([M-H]-, 100), 230 (18). HRMS (ESI-): calcd.
for C14H16NO3 [M-H]- 246.1124, found 246.1119; Rf = 0.28
(hexane/EtOAc 3:1).
1
light (254 nm). H NMR spectra were recorded at 300 MHz. 13C
NMR spectra and DEPT experiments were determined at 75
MHz. Chemical shifts are given in ppm relative to
tetramethylsilane (TMS), which is used as an internal standard,
and coupling constants (J) are reported in Hz. High Resolution
Mass Spectra (HRMS) were recorded using electrospray
ionization in negative ion mode or TOF MS in positive ion mode.
4.1.5.
1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-1-hydroxy-3-
1
4.1. General procedure for the synthesis α-hydroxy ketones 3 and
6:
methylpentan-2-one 3e: 0.17 g, 65%. Yellow oil. H NMR (300
MHz, CDCl3): δ 7.91-7.85 (m, 2 H), 7.61-7.45 (m, 6 H), 5.58 (s,
1 H), 5.56 (s, 1 H), 4.55 (dt, J = 14.8, 5.4 Hz, 2 H), 3.75-3.67 (m,
2 H), 3.60-3.53 (m, 2 H), 3.41-3.27 (m, 2 H), 2.80-2.64 (m, 2 H),
1.77 (s, 2 H), 1.75-1.42 (m, 2 H), 1.45-1.22 (m, 2 H), 1.05 (d, J =
6.7 Hz, 3 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.82 (t, J = 7.4 Hz, 3 H),
0.77 (t, J = 7.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 208.4 (2
x C), 169.1 (2 x C), 138.9 (C), 138.7 (C), 132.2 (CH), 132.1
(CH), 131.6 (2 x C), 129.3 (2 x CH), 124.5 (2 x CH), 122.4 (CH),
122.3 (CH), 70.5 (CH), 70.0 (CH), 44.5 (CH), 44.3 (CH), 44.2
(CH2), 43.5 (CH2), 30.1 (CH2), 29.9 (CH2), 26.9 (CH2), 25.1
(CH2), 17.6 (CH3), 15.4 (CH3), 11.9 (CH3), 11.3 (CH3). MS (ESI-
-TOF, m/z, %): 260 ([M-H]-, 100), 244 (22). HRMS (ESI-): calcd.
for C15H18NO3 [M-H]- 260.1287, found 260.1284; Rf = 0.31
(hexane/EtOAc 3:1).
A 0.1 M solution of SmI2 in THF (2.0 mmol, 2.0 equiv., 20
mL) was slowly added into a solution of the corresponding
distilled aldehyde 1 or ketone 5 (1.0 mmol, 1.0 equiv.) and N-2-
bromoethylphthalimide 2 (1.0 mmol, 1.0 equiv.) in dry THF (15
mL), followed by the addition of NiI2 (1 mol%, 2.5 mg). The
mixture was stirred at room temperature for 4 h. After that time,
the mixture was hydrolysed with an aqueous solution of HCl 1.0
M (15 mL). The final product was extracted with CH2Cl2 (3 x 20
mL). The organic layers were combined, filtered, dried over
Na2SO4 and concentrated under reduced pressure. α-Hydroxy
ketones 3 and 6 were purified by flash column chromatography
(hexane/EtOAc ranging between 3/1 and 5/1).
4.1.1. 1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-1-hydroxynonan-
2-one 3a: 0.23 g, 76%. Yellow oil. H NMR (300 MHz, CDCl3):
4.1.6.
(Z)-1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-2
1
1
hydroxyundec-8-en-1-one 3f: 0.24 g, 70%. Yellow oil. H NMR
(300 MHz, CDCl3): δ 7.74-7.45 (m, 4 H), 5.38-5.18 (m, 3 H),
4.62-4.45 (m, 1 H), 3.97-3.71 (m, 1 H), 3.64-3.41 (m, 2 H), 2.38-
2.15 (m, 2 H), 2.04-1.94 (m, 4 H), 1.51-1.18 (m, 6 H), 0.81 (t, J =
7.5 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ 205.5 (C), 168.9
(C), 138.92 (C), 133.1 (CH), 132.1 (CH), 131.4 (C), 129.4 (CH),
124.4 (CH), 122.6 (CH), 91.9 (CH), 70.4 (CH2), 42.1 (CH2), 37.3
(CH2), 30.5 (CH2), 29.5 (CH2), 27.3 (CH2), 25.0 (CH2), 20.9
(CH2), 14.8 (CH3). HRMS (ESI+): calcd. for C20H28NO3 [M+H]+
330.2069, found 330.2066; Rf = 0.36 (hexane/EtOAc 3:1).
δ 7.89-7.85 (m, 1 H), 7.60-7.43 (m, 3 H), 5.57-5.55 (m, 1 H),
4.51 (dt, J = 11.2, 5.6 Hz, 1 H), 3.70-3.61 (m, 1 H), 3.58-3.51 (m,
1 H), 3.44-3.35 (m, 1 H), 2.38-2.17 (m, 2 H), 1.51-1.41 (m, 2 H),
1.27-1.02 (m, 8 H), 0.81 (t, J = 6.7 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): δ 205.6 (C), 169.0 (C), 138.8 (C), 132.3 (CH), 131.3
(C), 129.3 (CH), 124.3 (CH), 122.4 (CH), 70.5 (CH), 43.9 (CH2),
33.2 (CH2), 31.4 (CH2), 29.3 (CH2), 28.7 (2 x CH2), 23.1 (CH2),
22.4 (CH2), 13.9 (CH3). MS (ESI--TOF, m/z, %): 302 ([M-H]-,
20), 286 (100), 240 (4). HRMS (ESI-): calcd. for C18H24NO3 [M-
H]- 302.1750, found 302.1748; Rf = 0.38 (hexane/EtOAc 3:1).
4.1.7. (E)-1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-2-hydroxy-4-
phenylbut-3-en-1-one 3g: 0.16 g, 52%. Yellow oil. 1H NMR (300
MHz, CDCl3): δ 8.02-7.21 (m, 10 H), 6.41-6.34 (m, 1 H), 5.63-
5.62 (m, 1 H), 4.17-3.93 (m, 1 H), 3.75-3.41 (m, 2 H), 3.33-3.29
(m, 1 H). 13C NMR (75 MHz, CDCl3): δ 194.3 (C), 169.5 (C),
149.1 (CH), 143.9 (C), 133.8 (C), 133.0 (CH), 131.9 (CH), 131.2
(CH), 129.5 (2 x CH), 129.2 (2 x CH), 124.6 (CH), 123.0 (CH),
116.3 (CH), 91.5 (C), 69.2 (CH), 42.5 (CH2), 28.2 (CH2). HRMS
(TOF MS ES+): calcd. for C19H18NO3 [M+H]+ 308.1287, found
308.1287; Rf = 0.34 (hexane/EtOAc 3:1).
4.1.2. 1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-1-hydroxyheptan-
2-one 3b: 0.21 g, 77%. Yellow oil. H NMR (300 MHz, CDCl3):
1
δ 7.87-7.84 (m, 1 H), 7.58-7.42 (m, 3 H), 5.35-5.33 (m, 1 H),
4.49 (dt, J = 14.6, 5.6 Hz, 1 H), 3.68-3.60 (m, 1 H), 3.57-3.50 (m,
1 H), 3.43-3.34 (m, 1 H), 2.34-2.16 (m, 2 H), 1.50-1.40 (m, 2 H),
1.21-0.99 (m, 4 H), 0.80 (t, J = 6.6 Hz, 3 H ). 13C NMR (75 MHz,
CDCl3): δ 205.5 (C), 169.0 (C), 138.8 (C), 132.2 (CH), 131.3
(C), 129.2 (CH), 124.2 (CH), 122.4 (CH), 70.5 (CH), 43.8 (CH2),
37.2 (CH2), 30.8 (CH2), 29.3 (CH2), 22.8 (CH2), 22.1 (CH2), 13.6
(CH3). MS (ESI--TOF, m/z, %): 274 ([M-H]-, 35), 258 (100), 205
(2). HRMS (ESI-): calcd. for C16H20NO3 [M-H]- 274.1443, found
274.1439; Rf = 0.34 (hexane/EtOAc 3:1).
4.1.8.
1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-2-hydroxy-2-
phenylethanone 3h: 0.11 g, 40%. Yellow oil. Data for the major
rotamer: 1H NMR (300 MHz, CDCl3): δ 7.68-6.92 (m, 9 H), 5.30
(s, 1 H), 4.30-3.99 (m, 2 H), 3.88-3.63 (m, 2 H). 13C NMR (75
MHz, CDCl3): δ 193.6 (C), 169.5 (C), 137.5 (C), 139.8 (C),
134.9 (C), 132.4 (CH), 129.9 (CH), 129.7 (2 x CH) 129.4 (2 x
CH), 124.9 (CH), 123.9 (CH), 123.1 (CH), 67.0 (CH), 44.3
(CH2), 32.1 (CH2). HRMS (TOF MS ES+): calcd. for C17H16NO3
[M+H]+ 282.1130, found 282.1127; Rf = 0.30 (hexane/EtOAc
3:1).
4.1.3. 1-Cyclohexyl-2-[2-(4,5-dihydrooxazol-2-yl)phenyl]-2-
1
hydroxyethanone 3c: 0.20 g, 71%. Yellow oil. H NMR (300
MHz, CDCl3): δ 7.91-7.88 (m, 1 H), 7.61-7.46 (m, 3 H), 5.54-
5.53 (m, 1 H), 4.54 (dt, J = 14.8, 5.4 Hz, 1 H), 3.73-3.65 (m, 1
H), 3.59-3.52 (m, 1 H), 3.38-3.28 (m, 1 H), 2.62-2.52 (m, 1 H),
1.80-1.42 (m, 6 H), 1.29-1.09 (m, 4 H). 13C NMR (75 MHz,
CDCl3): δ 207.7 (C), 169.0 (C), 138.8 (C), 132.1 (CH), 131.4
(C), 129.2 (CH), 124.3 (CH), 122.2 (CH), 69.7 (CH), 46.8 (CH2),
44.0 (CH), 30.0 (CH2), 29.7 (CH2), 27.5 (CH2) 25.5 (CH2), 25.3
(CH2), 24.8 (CH2). MS (ESI--TOF, m/z, %): 286 ([M-H]-, 100),
270 (9). HRMS (ESI-): calcd. for C17H20NO3 [M-H]- 286.1437,
found 286.1436; Rf = 0.38 (hexane/EtOAc 3:1).
4.1.9. 1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-2-hydroxy-2-(p-
tolyl)ethanone
3i:
0.14
g,
48%.
Yellow
oil.
Data for the major rotamer: 1H NMR (300 MHz, CDCl3): δ 8.10-
7.84 (m, 3 H), 7.62-7.03 (m, 5 H), 6.51 (s, 1 H), 4.63-4.41 (m, 1
H), 3.81-3.61 (m, 1 H), 3.66-3.31 (m, 2 H), 2.49 (s, 3 H). 13C
NMR (75 MHz, CDCl3): δ 192.7 (C), 169.2 (C), 143.9 (C), 140.1
(C), 133.4 (C), 132.3 (C), 131.9 (CH) 130.4 (2 x CH), 129.5 (2 x
CH), 124.6 (CH), 123.0 (CH), 122.3 (CH), 66.8 (CH), 44.1
4.1.4.
1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-1-hydroxy-3-
1
methylbutan-2-one 3d: 0.17 g, 69%. Colourless oil. H NMR
(300 MHz, CDCl3): δ 7.92-7.88 (m, 1 H), 7.60-7.46 (m, 3 H),
5.57-5.55 (m, 1 H), 4.56 (dt, J = 14.8, 5.3 Hz, 1 H), 3.74-3.66 (m,
4

(CH2), 31.0 (CH2), 21.3 (CH3). HRMS (ESI-): calcd. for
C18H16NO3 [M-H]- 294.1130, found 294.1129; Rf = 0.28
(hexane/EtOAc 3:1).
Thanks are due to Principado de Asturias (FICYT
IDI/2018/000181) for financial support. Partial financial support
by Arcelor Mittal (R&D-Principado de Asturias; FUO-286-18) is
gratefully acknowledged.
4.1.10. 1-[2-(4,5-Dihydrooxazol-2-yl)phenyl]-2-hydroxy-2-(4-
1
methoxyphenyl)ethanone 3j: 0.17 g, 55%. Yellow oil. H NMR
References and notes
(300 MHz, CDCl3): δ 8.05 (d, J = 8.1 Hz, 2 H), 7.92 (d, J = 7.0
Hz, 1 H), 7.48 (q, J = 7.7 Hz, 2 H), 7.31-7.19 (m, 1 H), 7.06 (d, J
= 9.3 Hz, 2 H), 6.46 (s, 1 H), 4.64-4.41 (m, 1 H), 3.95 (s, 3 H),
3.82-3.71 (m, 2 H), 3.65-3.45 (m, 2 H). 13C NMR (75 MHz,
CDCl3): δ 191.8 (C), 169.7 (C), 165.0 (C), 140.3 (C), 132.3
(CH), 131.8 (2 x CH), 129.5 (CH) 128.7 (C), 124.8 (CH), 123.0
(CH), 114.9 (2 x CH), 66.7 (CH), 56.1 (CH3) 44.3 (CH2), 31.0
(CH2). HRMS (TOF MS ES+): calcd. for C18H18NO4 [M+H]+
312.1236, found 312.1234; Rf = 0.25 (hexane/EtOAc 3:1).
1. (a) Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim.
1977, 1, 5-7. (b) Girard, P.; Namy, J. L.; Kagan, H. B. J.
Am. Chem. Soc. 1980, 102, 2693-2698.
2. (a) Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem.
2012, 77, 3049-3059. (b) Harb, Y. H.; Procter, D. J. Synlett
2012, 6-20. (c) Procter, D. J.; Flowers, R. A.; Skrydstrup, T.
Organic Synthesis using Samarium Diiodide: A Practical
Guide; RSC Publishing: Cambridge, 2009. (d) Edmonds, D.
J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371-
3404. (e) Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745-
777. (f) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96,
307-338. (g) Molander, G. A. Org. React. 1994, 46, 211-
367. (h) Molander, G. A. Chem. Rev. 1992, 92, 29-68.
3. (a) Szostak, M.; D. J. Procter, Angew. Chem. Int. Ed. 2012,
51, 9238-9256. (b) Plesniak, M. P.; Garduño-Castro, M. H.;
Lenz, P.; Just-Baringo, X.; Procter, D. J.; Nature Commun.
2018, 9, 4802-4810.
4. (a) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J.
Chem. Rev. 2014, 114, 5959-6039. (b) Aspinall, H. C.;
Greeves, N.; Valla, C. Org. Lett. 2005, 7, 1919-1922. (c)
Machrouhi, F.; Namy, J. –L. Tetrahedron Lett. 1999, 40,
1315-1318. (d) Annunziata, R.; Benaglia, M.; Cinquini, M.;
Raimondi, L. Eur. J. Org. Chem. 1999, 3369-3374.
5. Christensen, T. B.; Riber, D.; Daasbjerg, K.; Skrydstrup T.
Chem. Commun. 1999, 2051-2052.
6. Adinolfi, M.; Barone, G.; Iadosini, A.; Mangoni, L.; Manna,
R. Tetrahedron 1997, 53, 11767-11780.
7. Zhong, Y. -W.; Izumi, K.; Xu, M. -H.; Lin, G. -Q. Org. Lett.
2004, 6, 4747-4750.
8. (a) Gärtner P.; Knollmüller M.; Bröker J. Monatsh. Chem.
2003, 134, 1607-1615. (b) Aspinall H. C.; Greeves N.; Valla
C. Org. Lett. 2005, 7, 1919-1922.
9. McDonald, C. E.; Galka, A. M.; Green, A. I.; Keane, J. M.;
Kowalchick, J. E.; Micklitsch, C. M.; Wisnoski, D. D.
Tetrahedron Lett. 2001, 42, 163-166. (e) Xu, X.; Zhang, Y.
Tetrahedron 2002, 58, 503-506.
10. (a) Ha, D.-C. Tetrahedron Lett. 1996, 37, 2577-2580. (b)
Ha, D.- C.; Yun, C.-S.; Lee, Y. J. Org. Chem. 2000, 65,
621-623. (c) Yoda, H.; Matsuda, K.; Nomura, H.; Takabe,
K. Tetrahedron Letters 2000, 41, 1775-1779. (d) Farcas, S.;
Namy, J.-L. Tetrahedron Lett. 2001, 42, 879-882. (e) Yoda,
H.; Nakahama, A.; Koketsu, T.; Takabe, K. Tetrahedron
Letters 2002, 43, 4667-4669. (f) Chiara, J. L.; García, A.;
Cristóbal-Lumbroso, G. J. Org. Chem. 2005, 70, 4142-4151
(g) Vacas, T.; Álvarez, E.; Chiara, J. L. Org. Lett. 2007, 9,
5445-5448. (h) Kise, N.; Sakurai, T. Tetrahedron Lett. 2010,
51, 70-74.
11. Wallace, O.B.; Smith, D.W.; Deshpande, M.S.; Polson, C.;
Felsenstein, K.M. Bioorg. Med. Chem. Lett. 2003, 13, 1203-
1206.
12. Andrus M. B.; Hicken, E. J.; Stephens C. J.; Bedke, D. K. J.
Org. Chem. 2006, 71, 8651-8654.
4.1.11.
2-(4-Chlorophenyl)-1-[2-(4,5-Dihydrooxazol-2-
1
yl)phenyl]-2-hydroxyethanone 3k: 0.03 g, 10%. Yellow oil. H
NMR (300 MHz, CDCl3): δ 7.99-7.90 (m, 2 H), 7.57 (dd, J = 8.7
Hz, 2.3 Hz, 2 H), 7.53-7.43 (m, 2 H), 7.35-7.28 (m, 1 H), 7.21-
7.14 (m, 1 H), 6.43 (s, 1 H), 4.74-4.41 (m, 1 H), 3.80-3.34 (m, 3
H) 13C NMR (75 MHz, CDCl3): δ 192.6 (C), 169.5 (C), 141.6
(C), 139.4 (C), 134.2 (C), 134.0 (C), 132.5 (CH), 130.7 (2 x CH)
130.1 (2 x CH), 129.8 (CH), 125.0 (CH), 123.0 (CH), 67.1 (CH),
44.5 (CH2), 31.2 (CH2). Rf = 0.28 (hexane/EtOAc 3:1). HRMS
(TOF MS ES+): calcd. for C17H15ClNO3 [M+H]+ 316.0740,
found 316.0737; Rf = 0.25 (hexane/EtOAc 3:1).
4.1.12.
[2-(4,5-Dihydrooxazol-2-yl)phenyl]-2-ethyl-2-
hydroxybutan-1-one 6a. 0.15 g, 56%. Yellow oil. Data for the
1
major rotamer: H NMR (300 MHz, CDCl3): δ 7.78-7.69 (m, 2
H), 7.58-7.56 (m, 2 H), 4.27-4.20 (m, 1 H), 4.17-4.09 (m, 1 H),
3.91-3.82 (m, 1 H), 3.56-3.44 (m, 1 H), 1.64-1.25 (m, 4 H), 1.23
(t, 3 H, J = 7.2 Hz), 0.85 (t, 3 H, J = 7.2 Hz). 13C NMR (75 MHz,
CDCl3): δ 175.6 (C), 147.4 (C), 133.4 (CH), 133.1 (C), 130.3
(CH), 124.7 (CH), 124.5 (CH) 104.9 (C), 78.3 (C), 70.4 (CH2),
46.1 (CH2), 39.1 (CH2), 21.3 (CH3), 16.7 (CH2), 15.1 (CH3).
HRMS (TOF MS ES+): calcd. for C15H19NNaO3 [M+Na]+
284.1257, found 284.1257; Rf = 0.40 (hexane/EtOAc 1:1).
4.1.13.
[2-(4,5-Dihydrooxazol-2-yl)phenyl](1-
1
hydroxycyclopentyl)methanone 6b. 0.16 g, 62%. Yellow oil. H
NMR (300 MHz, CDCl3): δ 7.88-7.85 (m, 1 H), 7.78-7.75 (m, 1
H), 7.62-7.49 (m, 2 H), 4.28-4.19 (m, 2 H), 4.00-3.91 (m, 1 H),
3.57-3.47 (m, 1 H), 1.89-1.52 (m, 4 H), 1.34-1.27 (m, 2 H), 0.96-
0.91 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ 175.6 (C), 147.3
(C), 133.2 (CH), 132.2 (C), 129.9 (CH), 124.6 (CH), 123.9 (CH)
102.8 (C), 77.2 (C), 69.5 (CH2), 45.6 (CH2), 36.6 (CH2), 35.2
(CH2), 23.8 (CH2), 23.2 (CH2). HRMS (TOF MS ES+): calcd.for
C15H18NO3 [M+H]+ 260.1281, found 260.1281; Rf = 0.28
(hexane/EtOAc 3:1).
4.1.14.
[2-(4,5-Dihydrooxazol-2-yl)phenyl]-1-
1
hydroxycyclohexyl)methanone 6c. 0.18 g, 65%. Yellow oil. H
NMR (300 MHz, CDCl3): δ 7.83 (d, 1 H, J = 7.5 Hz), 7.76 (d, 1
H, J = 7.4 Hz), 7.58 (td, 1 H, J = 7.5, 1.4 Hz), 7.50 (td, 1 H, J =
7.4, 1.2 Hz), 4.25-4.14 (m, 2 H), 3.88 (ddd, 1 H, J = 11.2, 8.0, 6.8
Hz), 3.50 (ddd, 1 H, J = 11.2, 9.9, 7.2 Hz), 1.86-1.81 (m, 1 H),
1.68-1.44 (m, 5 H), 1.38-1.22 (m, 3 H), 1.13-1.04 (m, 1 H). 13C
NMR (75 MHz, CDCl3): δ 175.5 (C), 147.0 (C), 133.0 (CH),
132.4 (C), 129.8 (CH), 124.9 (CH), 124.0 (CH) 104.2 (C), 76.7
(C), 69.6 (CH2), 46.0 (CH2), 32.6 (CH2), 31.0 (CH2), 25.5 (CH2),
21.2 (CH2), 21.0 (CH2). HRMS (TOF MS ES+): calcd. for
C16H20NO3 [M+H]+ 284.1438, found 274.1433; Rf = 0.25
(hexane/EtOAc 3:1).
13. Roush W. R.; Hartz, R. A.; Gustin, D. J. J. Am. Chem. Soc.
1999, 121, 1990-1991.
14. Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayake,
C. H.; Wald, S. A. Tetrahedron: Asymmetry 2000, 11, 3659-
3663.
Acknowledgments
15. Rogers, P.L.; Shin, H.S.; Wang, B. Adv. Biochem.
Engin./Biotechnol. 1998, 59, 43-58.
5

16. Liu, J.; Yang, S.; Tang, W.; Yang, Z.; Xu, J. Green Chem.
2018, 20, 2118-2124.
2018, 74, 5475-5480. (c) Concellón, J. M.; Rodríguez-Solla,
H.; Concellón, C.; del Amo, V. Chem. Soc. Rev. 2010, 39,
4103-4113. (d) Concellón, J. M.; Rodríguez-Solla, H. Eur.
J. Org. Chem. 2006, 1613-1625. (e) Concellón, J. M.;
Rodríguez-Solla, H. Chem. Soc. Rev. 2004, 33, 599-609.
30. (a) Machrouhi, F.; Hamann, B.; Namy, J. L.; Kagan, K. B.
Synlett. 1996, 7, 633-634. (b) Choquette, K.A.; Sadasivam,
D. V.; Flowers, R. A. J. Am. Chem. Soc. 2011, 133, 10655-
10661.
31. Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett.
1983, 24, 765-766.
32. Li, T.; Cui, W.; Liu, J.; Zhao, J.; Wang, Z. Chem. Commun.
2000, 139-140.
17. (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247-4250.
(b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2003, 125, 10808-10809. (c)
Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.;
Urushima, T.; Shoji, M.; Hashizume, D.; Koshino, H. Adv.
Synth. Catal. 2004, 346, 1435-1439. (d) Sibi, M. P.;
Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124-4125. (e)
Palomo, C.; Vera, S.; Velilla, I.; Mielgo, A.; Gomez-
Bengoa, E. Angew. Chem., Int. Ed. 2007, 46, 8054-8056. (f)
Chen, C.; Feng, X.; Zhang, G.; Zhao, Q.; Huang, G.
Synthesis 2008, 3205-3208. (g) Gotoh, H.; Hayashi, Y.
Chem. Commun. 2009, 3083-3085. (h) Koike, T.; Akita, M.
Chem. Lett. 2009, 38, 166-167. (i) Poe, S. L.; Bogdan, A.
R.; Mason, B: P.; Steinbacher, J. L.; Opalka, S. M.;
McQuade, D. T. J. Org. Chem. 2009, 74, 1574-1580.
18. (a) Miescher, K.; Schmidlin, J. Helv. Chim. Acta 1950, 33,
1840-1847. (b) Brain, E. G.; Cassidy F.; Lake, A. W.; Cox,
P. J.; Sim, G. A. J. Chem. Soc., Chem. Commun. 1972, 497-
498. (a) Baskara, S.; Das, J.; Chandrasekaran, S. J. Org.
Chem. 1989, 54, 5182-5184. (b) Takai, T.; Yamada, T.;
Mukaiyama, T. Chem. Lett. 1991, 1499-1502.
19. (a) Plietker, B. Tetrahedron: Asymmetry 2005, 16, 3453-
3459. (b) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92,
919-934.
20. (a) Rose, C. A.; Gundala, S.; Connon, S. J.; Zeitler, K.,
Synthesis 2011, 190-198. (b) O’Toole, S. E.; Rose, C. A.;
Gundala, S.; Zeitler, K. Connon, S. J. J. Org. Chem. 2011,
76, 347-357.
21. Tsuda, M.; Yamakawa, M.; Oka, S.; Tanaka, Y.; Hoshino,
Y.; Mikami, Y.; Sato, A.; Fujiwara, H.; Ohizumi, Y.;
Kobayashi, J. J. Nat. Prod. 2005, 68, 462-464.
22. (a) Onishi, H. R.; Pelak, B. A.; Silver, L. L.; Kahan, F. M.;
Chen, M.-H.; Patchett, A. A.; Galloway, S. M.; Hyland, S.
A.; Anderson, M. S.; Raetz, C. R. H. Science 1996, 274,
980-982. (b) A. Mukai, A.; Fukai, T.; Matsumoto, M.;
Ishikawa, J.; Hoshino, Y.; Yazawa, K.; Harada, K.; Mikami,
Y. J. Antibiot. 2006, 59, 366-369.
23. Li, Q.; Woods, K. W.; Claireborne, A.; Gwanltey, S. L., II;
Barr, K. J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hua Hui, Y.;
Lee, J.; Warner, R. B.; Kovar, P.; Nukkla, M. A.; Zielinski,
N. A.; Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.;
Frost, D.; Ng, S.-C.; Rosenberg, S.; Sham, H. L. Bioorg.
Med. Chem. 2002, 12, 465-469.
24. Vizi, E. S. Med. Res. Rev. 1986, 6, 431-449.
25. (a) Padmaja, A.; Rajasekhar, C.; Durgamma, S.; Venkatesh,
B. C.; Padmavathi, V. Med. Chem. Res. 2014, 23, 1084-
1098. (b) Garg, P.; Chaudhary, S.; Milton, M. D. J. Org.
Chem. 2014, 79, 8668-8677.
26. (a) Khumsubdee, S.; Fan, Y.; Burgess, K. J. Org. Chem.
2013, 78, 9969-9974. (b) Mckeon, S. C.; Muller- Bunz, H.;
Guiry, P. J. Eur. J. Org. Chem. 2011, 7107-7115. (c)
Sawada, T.; Nakada, M. Adv. Synth. Catal. 2005, 347, 1527-
1532.
27. (a) Herasymchuk, K.; Huynh, J.; Lough, A. J.; Fernández, L.
R.; Gossage, R. A. Synthesis 2016, 2121-2129. (b)
Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505-
2550.
28. (a) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-
2360. (b) R. Mei, L. Ackermann, Adv. Synth. Catal. 2016,
358, 2443-2448.
29. (a) Soto, M.; Soengas, R. G.; Silva, A. M. S.; Gotor-
Fernández, V.; Rodríguez-Solla, H. Chem. Eur. J. 2019, 25,
13104–13108. (b) Soto, M.; Soengas, R. G.; Silva, A. M. S.;
Gotor-Fernández, V.; Rodríguez-Solla, H. Tetrahedron
6

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: