A Zinc enolate of amide: Preparation and application in reformatsky-like reaction leading to β-hydroxy amides

Full text of DOI:10.1002/bkcs.10224

Note
DOI: 10.1002/bkcs.10224
BULLETIN OF THE
H.-H. Cho and S.-H. Kim
KOREAN CHEMICAL SOCIETY
A Zinc Enolate of Amide: Preparation and Application in
Reformatsky-like Reaction Leading to β-Hydroxy Amides
*
Hyun-Hee Cho and Seung-Hoi Kim
Department of Chemistry, Dankook University, Cheonan 330-714, Korea.
*E-mail: kimsemail@dankook.ac.kr
Received November 15, 2014, Accepted December 15, 2014, Published online March 24, 2015
Keywords: Zinc amide, Cross-coupling, Active zinc, β-Hydroxy amide, Reformatsky-like reaction
One of the best known functionalized organic complexes is
the β-hydroxy carbonyl compound. This unique functionality
has been frequently found in naturally occurring bioactive
derivatives.1 Among complexes that contain two particular
functionalities, β-hydroxy amides have been especially con-
sidered as valuable subunits for natural-products synthesis.2
To construct the proper structure of 1,3-functionalities, aldol
condensation is the most versatile method. In general, this
methodology consists of the nucleophilic addition of enolate
to carbonyl compounds. Consequently, the classical Refor-
matsky reaction has played a powerful role as one of the prac-
tical metallic enolates.3 In this reaction, zinc enolates of esters,
which were mostly generated from α-halo carbonyl com-
pounds, were commonly used.
Considering the classical Reformatsky reaction, we antici-
pated that thecoupling reaction of zincenolates ofamides with
a carbonyl compound could be utilized for the synthesis of
β-hydroxy amides. More interestingly, this goal could be eas-
ily achieved when the corresponding zinc enolates of amides
are readily available.
in this work, coupling reactions with any carbonyl compounds
has not been investigated. Instead, the study focused only on
α-arylation of zinc enolates of amides.
Here, we report the easy preparation of a room-temperature-
stable zinc enolate of amide in tetrahydrofuran (THF) from
α-chloroamideanditssubsequentcoupling reactionswith car-
bonyl derivatives – a Reformatsky-type reaction.
Toexecutetheutilityofaneworganozincreagent, ourstudy
started with N,N-diethylchloroacetamide, which is readily
available, for the preparation of zinc enolate of amide. The
α-chloro amide was treated with highly active zinc (Zn∗) pre-
pared by the literature procedure.8 The oxidative addition of
zinc into the carbon–chlorine bond was completed in 4 h at
ambient temperature. To confirm the formation of the corre-
sponding (2-(diethylamino)-2-oxoethyl)zinc chloride, iodine
quenching of A was carried out, and GC-MS analysis of the
aliquot showed over 95% conversion to the corresponding
N,N-diethyliodoacetamide. Delighted with this result, we fur-
ther examined the reactivity of A by a cross-coupling reaction
with carbonyl compounds (Scheme 1).
To date, very limited examples such as the use of α-bromo
amide4 and alkali metal amide enolate5 have been reported for
the preparation of zinc enolates of amides. Unfortunately,
there was generally low usage of zinc enolate of amides in pre-
vious studies. Also, scattered examples of zinc enolate of
amide usage have been found, and very limited numbers of
β-hydroxy amide complexes have been prepared through
the Reformatsky-like reaction. In the majority of cases, the
reactive species, zinc enolate, was prepared in situ.6
Recently, Hartwig's group reported a study on the prepara-
tion and arylation of both isolated and in situ zinc enolates of
amides generated from α-bromo amides.7 Although pioneer-
ing exploration of zinc enolate of amides has been conducted
The cross-coupling reaction of A with aldehydes were car-
ried out in the absence of any catalyst and completed in most
cases within 1.0 h at room temperature. To our delight, the cor-
responding β-hydroxy amides were obtained with moderate to
good isolated yields (Table 1). As expected, a variety of aro-
matic aldehydes (entries 1–6, Table 1) were easily coupled
with A, resulting in the formation of the corresponding
β-hydroxy amides (1a–1f). Regardless of the substituent on
the aromatic ring, moderate isolated yields were consistently
obtained. It should be emphasized that functional groups such
as nitrile (entry 4, Table 1) and nitro (entry 6, Table 1) were
tolerated by the novel organozinc reagent A. Not only aro-
matic aldehydes but also aliphatic aldehydes were excellent
Scheme 1. Preparation and coupling reaction of zinc enolate of amide.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1274–1277
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substrates to react with A under mild conditions. The corre-
sponding products (1g–1j) were also achieved in moderate
yields (entries 7, 9, and 10, Table 1) except n-pentanal
(37%, entry 8). 2-Thiophene carbaldehyde coupled well with
A to give rise to the corresponding product (1k) in 66% iso-
lated yield (entry 11, Table 1). It was of interest that 2-
furaldehyde and its derivatives were also suitable for the
Reformatsky-like reaction, and the desired coupling products
were successfully formed. Coupling of A with both furfural
and 5-bromofurfural was executed, and the desired alcohols
(1l and 1m) were obtained in 50% and 71% isolated yields,
respectively (entries 12, and 13, Table 1). Further study was
conducted with highly conjugated furfural derivatives (entries
14–17, Table 1), leading to the complicated β-hydroxy amides
(1n–1q) in moderate to excellent yields.
study was executed with a wide variety of ketones, and the
results are summarized in Table 2. The initial attempts were
conducted with aromatic ketones bearing either an electron-
withdrawing or electron-donating group. A nice conversion
into the corresponding β-hydroxy amides (2a and 2b) was
observed (entries 1–2, Table 2) in good yields. For nitro-
Table 2. Coupling reaction of A with ketones
.
Entry
1
Ketone
Product
Yielda
79
2a
With these promising results in hand, the investigation was
expanded to see if this protocol could be used for a much
broader range of carbonyl compounds. With this aim, the
2b
3
2b
2c
82
Table 1. Coupling reaction of A with aldehydes
nrc
4
5
6
7
8
2d
2e
2f
64
76
66
94
55
.
Entry
Ar(R)CHO
Product
Yielda
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
55
55
59
40
60
56
57
2g
2h
1g
8
9
1h
1i
37
60
9
2i
70
10
1j
63
10
11
2j
44
43
11
12
13
14
1k
1l
66
50
71
95
2k
1m
1n
12
13
2l
50
34
15
16
1o
1p
49
65
2m
14
15
2n
2o
38
85
17
18
1q
1r
86
65
a Isolated yield (based on ketone).
b Catalytic amount of TMEDA used.
c No coupling took place.
a Isolated yield (based on aldehyde).
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substituted ketone, a catalytic amount of TMEDA was
required to complete the reaction. A drawback was observed
from the coupling reaction of A with a heavily hindered ketone
(entry 3, Table 1). No coupling reaction took place under
the conditions depicted in Table 1. To expand the general
applicability of this protocol, we next sought to perform
a more challenging coupling, which was accomplished
with heteroaromatic ketones. Since the Mineno group9
reported a double Reformatsky reaction especially with
2-benzoylpyridine in slightly different conditions from ours,
it was of interest to compare the results. As seen in the results
depicted in Table 2, we were pleased to observe the formation
of the mono-adducts (2d–2f) in good yields. More heteroaro-
matic ketones (entries 7–9, Table 2) bearing thiophene, furan,
pyrone, and oxazole rings were coupled well, furnishing var-
ious tertiary alcohol products (2g–2i).
In conclusion, we have developed an efficient synthetic
route for the preparation of β-hydroxy amides.10 The method
involved the preparation of room-temperature-stable organo-
zinc reagents (A, B, and C) in THF and their subsequent cou-
pling reactions with various carbonyl derivatives under mild
conditions. Significantly, this approach using zinc enolate
of amides could expand the scope of Reformatsky-like reac-
tions. Further studies to elucidate this synthetic protocol are
currently under way in our laboratory.
Acknowledgment. This work was supported bytheIndustrial
Strategic Technology Development Program (No. 10043047,
Development of highly efficient dyes for Green and Yellow
hybrid color resist) funded by the Ministry of Trade, Industry
and Energy (MOTIE, Republic of Korea).
Coupling reactions of A with heteroaromatic alkyl ketones
(entries 10 and 11, Table 2) took place successfully and
resulted in the formation of the expected β-hydroxy amides
(2j and 2k). From the results observed above, we anticipated
that the coupling reaction of A with relatively simple ketones
could be easily accomplished to give rise to hydroxyl amides.
Thus, several readily available ketones (entries 12–15,
Table 2) were employed in the coupling reactions, leading
to the products (2l–2o) in moderate yields.
Toinvestigatethegenerality ofthisstrategy, moreexamples
of zinc enolate of amides were prepared and coupled with car-
bonyl compounds. As described in Table 3, zinc enolates (B
and C) were easily prepared utilizing the aforementioned con-
ditions. Then, the obtained zinc enolates were applied to the
Reformatsky-like reaction, affording the corresponding
β-hydroxy amides in moderate yields. As mentioned above,
1.2 equiv and 2.0 equiv of zinc enolate (B or C) were
employed in the reactions with aldehydes and ketones, respec-
tively. The results are described in detail in Table 3.
References
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A. Pérez-Encabo, Tetrahedron Lett. 2000, 56, 1217; For Et2Zn-
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son, S. Couve-Bonnaire, P. Jubault, X. Pannecouke, Eur.
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Table 3. More examples.
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10. Representative procedures: Preparation of (2-(diethylamino)-2-
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Number in parenthesis is isolated yield (based on aldehyde or ketone).
Bull. Korean Chem. Soc. 2015, Vol. 36, 1274–1277
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bottomed flask equipped with a stir bar was added 5.23 g of
NaHCO3, Na2S2O3 solution, and brine, and then dried over
anhydrous MgSO4. Purification by column chromatography
on silica gel (10% ethyl acetate/90% heptane) afforded 0.30 g
of N,N-diethyl-3-hydroxy-3-(4-nitrophenyl)propanamide (1f)
in 56% isolated yield as an off-white solid (m.p. 103–105 ꢀC);
1H NMR (CDCl3, 500 MHz) δ = 8.21 (d, J = 8.5 Hz, 2H), 7.59
(d, J = 8.5 Hz, 2H), 5.29 (br s, 1H), 5.24 (d, J = 10.0 Hz, 1H),
3.40 (dq, J = 7.5, 2.0 Hz, 1H), 3.25 (dq, J = 7.5, 2.0 Hz, 1H),
2.73 (dd, J = 16.0, 3.0 Hz, 1H), 2.58 (dd, J = 16.0, 10.0 Hz,
1H), 1.16 (t, J = 7.5 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ
= 170.72, 150.62, 147.20, 126.60, 123.94, 69.86, 42.00,
41.32, 40.35, 14.09, 13.29. IR (KBr): ṽ = 3320 (br), 2950,
active zinc (Zn∗, 80.0 mmol). N,N-Diethylchloroacetamide
(8.98 g, 60.0 mmol) was cannulated neat into the flask in an
ice bath. The resulting mixture was then stirred for 4.0 h at ambi-
ent temperature. The whole mixture was settled down and then
the supernatant was used for the subsequent coupling reactions.
(b) Cross-coupling reaction of A. Into a 25-mL round-bottomed
flask was placed 4-nitrobenzaldehyde (0.30 g, 2.0 mmol) and
then 2.0 mL of THF was added into the flask under an argon
atmosphere. Next, (2-(diethylamino)-2-oxoethyl)zinc chloride
(5.0 mL, 0.5 M in THF, 2.5 mmol) was added, stirred at room
temperature for 1.0 h, quenched with saturated NH4Cl solution,
extracted with ethyl ether (10 mL × 3), washed with saturated
2900, 1630, 1500, 1340 cm−1
.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1274–1277
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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