Synthesis of α-Functionalized Trichloromethylcarbinols

Article abstract of DOI:10.1021/acs.joc.5b01547

A new series of α-functionalized trichloromethylcarbinols have been synthesized from corresponding α-halomethyl ketones, esters, and amides in 48-78% overall yields. Reactivity of nitrates obtained in the first step was dependent on the electron-withdrawi

Full text of DOI:10.1021/acs.joc.5b01547

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Synthesis of alpha-functionalized trichloromethylcarbinols
Ram Nath Ram, and Vineet Kumar Soni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01547 • Publication Date (Web): 11 Aug 2015
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Synthesis of α-functionalized trichloromethylcarbinols
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Ram N. Ram and Vineet Kumar Soni*
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Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi-110016, India
A new series of α-functionalized trichloromethylcarbinols have been
synthesized from corresponding α-halomethyl ketones, ester and
amides in 48-78% overall yields. Reactivity of nitrates obtained in
the first step was dependent on the electron-withdrawing nature of
the functional groups, and increases with increasing electron
deficiency. Synthetic applications of such trichloromethylcarbinols for the preparation of chloromethyl-α-diketones,
trichloromethylated dihydrofurans and enol acetates of α-functionalized acid chlorides have been demonstrated. The reaction of
these compounds in the Jocic-Reeve reaction was also demonstrated.
Trichloromethylcarbinols have been widely appreciated over their use in several useful transformations.1 The formation of α-
amino acids,2 α-substituted carboxylic acids/amides,3 heterocycles4 and substituted enoic acids5 was realized owing to their
tendency to form a gem-dichloroepoxide intermediate in the presence of a strong base followed by the ring opening by a
nucleophile (such as amines,2a,2g,4c,4f azide,2b-f,4d-e hydroxide,3a-b alcohols,3e,5 phenols,3c thiols,5 fluoride,3e cyanide,3e cyanate,3e
hydride,3f selenide,3f,3h pyrroles,3g thiourea4b). Trichloromethylcarbinols can be converted into epoxides,6 vinyl dichlorides,7
alkynes,8 chloromethyl ketones,8a,9 2-haloalk-2(Z)-en-1-ols and 1-chloro-1(Z)-alkenes,10 and ring-expanded ketones by the reaction
of cyclic trichloromethylcarbinols with aldehydes.11 The synthesis of trichloromethylcarbinols has been realized by the reaction of
various simple aldehydes and ketones with chloroform in the presence of a base,12 such as sodium or potassium hydroxide,12a-d,12g
amidines12h and lithium dicyclohexylamide.12e-f Electroreduction of CCl4 in the presence of carbonyl compounds has also been
studied.13 Additionally, milder methods involving CCl3COOH,14 CCl3COOH/CCl3COONa15 have been developed. However,
trimethylsilyl-protected trichloromethylcarbinols were prepared from either trimethyl(trichloromethyl)silane (TMSCCl3) in the
presence of a catalyst,16 such as TBAF,16a TASF16b and sodium formate,16c thermally17 or trimethylsilyl trichloroacetate with
K2CO318 and KF.19 Due to the volatility and sublimation of TMSCCl3, methods were developed using TMSCl/CCl4/Mg/HMPT20 or
TMSCl/CHCl3/LiHMDS/Bu4NOAc,21 where it was in situ formed. One-pot synthesis of trichloromethylcarbinols from primary
alcohols has also been reported,22 where Dess−Martin periodinane (DMP) was used as an oxidant and CHCl3/TBD for the
transformation of resulting aldehydes into trichloromethylcarbinols. Recently, an improved method for the preparation of
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trichloromethylcarbinols from enolizable ketones using CHCl3/TiCl(Oi-Pr)3/BuLi has been developed.23 Decarboxylative
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trichloromethylation of aromatic aldehydes and its application in continuous flow have also been explored.24
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However, there is no report for the synthesis of α-functionalized trichloromethylcarbinols i.e. 3,3,3-trichloro-2-hydroxy ketones,
esters or amides using trichloromethyl anion as a nucleophile. The aldehyde precursors for these molecules immediately convert
into hydrate in the presence of moisture25 and prone to oxidation and polymerization.25b Also, selective addition to one carbonyl is
doubtful for dicarbonyl compounds. Moreover, the construction of such molecules using other methods has not been much
explored.26 Methods for the synthesis of such molecules include (i) the reaction of chloral with HCN to form adduct which is
further hydrolyzed to give β,β,β-trichlorolactic acid and esterified to give β,β,β-trichlorolactates26e otherwise β,β,β-
trichlorolactamide derivatives26b by controlled hydrolysis or by direct reaction of this adduct with phenol in presence of AlCl3
derivatives to give aryl β,β,β-trichlorolactates26b,26d (ii) Passerini reaction for the synthesis of trichlorolactamides by reaction of
isocynides with chloral hydrate26a,26c,26g (iii) from isocynides with trichloroacetic acid anhydride26f to produce hydrates of
trichloropyruvamides. Toxicity of CN- ion is the major drawback of the first method whereas difficult preparation and purification27
and extremely distressing odour27a of isocynides bring insignificance to last two methods. O-Methyl protected methyl
trichlorolactate was also prepared by the reaction of ketene silyl acetals with carbon tetrachloride.28 In one report, N-
(methoxymethyl)-N,1,1,1-tetramethylsilanecarboxamide was reacted with chloral to provide corresponding O-trimethylsilyl
protected or unprotected trichlorolacamide.29 The electrolysis of 9,10-phenanthrenequinone in the presence of benzenediazonium
tetrafluoroborate in chloroform provided 10-hydroxy-10-(trichloromethyl)phenanthren-9(10H)-one in low yield.30 Such compounds
are found to be biologically active as β,β,β-trichlorolactamide is effective against plant growth both pre- (mustard: dicot) and post-
germinative (celery, tomatoes, coleus: dicots),26b while isopropyl β,β,β-trichlorolactate was active against cereal grains
(monocots).26b However, due to the limited accessibility such compounds have not been comprehensively studied.
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In view to the importance of trichloromethylcarbinols in the synthesis of a variety of building blocks as well as the utility of such
structural unit in total synthesis, it was considered worthwhile to develop a general, efficient and practical method for the synthesis
of α-functionalized trichloromethylcarbinols. It was expected that the easy access to such compounds would enhance the synthetic
applications of trichloromethylcarbinols further. Herein, a facile synthesis of such trichloromethylcarbinols 2 by a direct two step-
pathway starting from α-halomethyl ketones, esters and amides 1 has been reported. The method is quite general, which involves
nucleophilic substitution of halo group (Br, I) by a nitrate group in acetonitrile at room temperature25a,31 followed by its treatment
with sodium trichloroacetate in DMF at 5−25 ˚C to give the desired products in moderate to high yields (Table 1). Resulting
precipitate of silver halide in the first step was removed by filtration and the nitrates, obtained from the filtrate were used without
further purification. Attempts were made to achieve one-pot synthesis of the 2a by step-wise addition of the reagents AgNO3 and
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CCl3COONa to a solution of 1a in acetonitrile as well as in DMF at 20-25 ˚C. However, the reactions resulted in the formation of
mixtures of unidentified products. The presence of AgBr thus formed during the reaction might have interfered in the next step.
Additionally, the possible competition of trichloromethyl anion and nitrate particularly in DMF could be the reason for the
complication. Almost all the products are solid (except 2h) and stable under atmospheric conditions. These
trichloromethylcarbinols were further investigated under some transformations in view to their importance.
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Table 1. Synthesis of α-Functionalized Trichloromethylcarbinols 2a-la
Entry
1
Z
R
X
time
yield
(%)
2
step 1
(h)
10
step 2
(min)
20
1
2
a
C6H5
H
H
Br
Br
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78
b
p-Me-C6H4
10
30
3
4
c
d
e
f
p-MeO-C6H4
p-Br-C6H4
m-O2N-C6H4
C6H5
H
H
Br
Br
Br
Br
I
10
10
10
10
10
10
12
16
30
10b
5b
74
64
60c
60
60
48
75
68
5
H
6
Me
H
60
10
60
60
90
7
g
h
i
2-furyl
8
n-hexyl
H
I
9
C2H5O
H
Br
Br
10
j
H
11
12
k
(i-Pr)2N
H
H
Br
Br
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16
90
90
66
65
l
Ph(Me)N
b
aAll the reactions were performed by taking 1 (2 mmol), AgNO3 (2 mmol), CCl3COONa (4 mmol) at room temperature (20-25˚C). The temperature was
maintained at 0-5 ˚C. c3,3,3-Trichloro-2-hydroxy-2-(3-nitrophenyl)propyl nitrate 3 was also obtained in 18% isolated yield.
In all cases, reaction completion was confirmed by TLC. Relative observations revealed that the reactivity of nitrates increases as
the electron-withdrawing nature of the substituted group increases (keto>ester>amide). Aromatic keto-nitrates were more reactive
than aliphatic keto-nitrates, in which, electron donating groups like Me, OMe at aromatic ring (entry 2, 3) decreased the reactivity
to some extent and required additional time for the completion of the reaction. On the other hand, electron withdrawing groups like
Br, NO2 (entry 4, 5) enough activated the substrate to react at 0-5 ˚C and the reaction was complete in 5-10 min. Interestingly, m-
nitro group of 1e also activated the keto group to react with trichloromethyl anion to give 3,3,3-trichloro-2-hydroxy-2-(4-
nitrophenyl)propyl nitrate 3 along with the expected product 2e in 18% isolated yield. Further reaction of the nitratomethyl group of
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3 did not occur, probably due to its reduced reactivity towards base-promoted elimination reaction. A mechanism for the formation
of trichloromethylcarbinols has been proposed (Scheme 1). The necessity of two equivalents of sodium trichloroacetate could be
explained on the basis of possible consumption of one equivalent of sodium trichloroacetate during the elimination of HNO2 in
second step or slow decomposition of trichloromethyl anion. Remaining one equivalent was required for trichloromethylation of
carbonyl group.
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Scheme 1. Proposed Mechanism for the Formation of Trichloromethylcarbinols 2
Incidentally, the reaction of the nitrate of 1l with excess of sodium trichloroacetate (3 equiv) occurred vigorously with an
increase in the reaction temperature and resulted in the formation of an interesting compound 4 (Scheme 2) in 54% isolated yield. It
appeared that two molecules of the normal product 2l, initially formed were involved in its formation. A probable mechanism for its
formation is proposed which involves oxidation of one molecule of 2l with dichlorocarbene formed from excess sodium
trichloroacetate (Scheme 2). The formation of dichlorocarbene might have been facilitated by considerable amount of heat
generated during the exothermic decarboxylation of excess of the trichloroacetate. The intermediacy of 2l was further supported by
the reaction of 2l with 2 equiv of sodium trichloroacetate in DMF under similar conditions which provided the same product 4 in
62% yield. With lower amount (1 or 1.5 equiv) of sodium trichloroacetate, the reaction of 2l was not complete. Probably, an
–
equivalent of CCl3 generated from the decarboxylation of the trichloroacetate was required to act as a base to facilitate the
oxidation of 2l with dichlorocarbene. The oxidation of alkoxides to aldehydes or ketones by hydride transfer to dichlorocarbene
1
(generated from chloroform and NaOH) is reported in the literature.32 The formation of the compound 4 was supported by IR, H
NMR, 13C NMR spectroscopy HRMS data. The structure of 4 was also supported by single crystal X-ray diffraction data (see
supporting information).
Scheme 2. Formation of 4 with Excess Sodium Trichloroacetate
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α-Functionalized trichloromethylcarbinols obtained above are important synthetic intermediates. In order to demonstrate the
synthetic importance of the trichloromethylcarbinols 2, 3,3,3-trichloro-2-hydroxy-1-phenyl- propane-1-one 2a as a representative
member of 2 was treated with CuCl/bpy (2 equiv each) in refluxing DCE under nitrogen atmosphere for 1 h to give 3-chloro-1-
phenylpropane-1,2-dione 5 in 65% isolated yield (Scheme 3). The reaction was considerably faster than that of simple
trichloromethylcarbinols observed earlier, which required 3 h for completion.9
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Scheme 3. Synthesis of 3-Chloro-1-phenylpropane-1,2-dione 5
The formation of dihydrofuran by the reaction of 3-hydroxybutan-2-one with dimethyl acetylenedicarboxylate (DMAD) is
reported in literature.33 The application of the α-functionalized trichloromethylcarbinols 2 in the synthesis of highly substituted and
functionalized dihydrofurans was demonstrated by the reaction of 2a (Scheme 4) with DMADC in the presence of K2CO3 in
refluxing tetrahydrofuran. This resulted in the formation of the 4,5-dihydrofuran derivative 6 containing a trichloromethyl group
with complete diastereoselectivity in 72% isolated yield, where the bulky trichloromethyl group positioned itself trans to the phenyl
group. An intramolecular Cl…H bonding might also be contributing to the selectivity. The structure of 6 was also supported by
single crystal X-ray diffraction data (see supporting information).
Scheme 4. Synthesis of Dihydrofuran 6 from 2a and DMADC
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As reported by our laboratory34 O-acetylated trichloromethylcarbinols undergo dechlorinative Surzur-Tanner rearrangement
involving 1,2-acyloxy shift on treatment with CuCl/bpy to the diastereoselective formation of enol acetates of acid chlorides. The
application of this reaction for stereoselective synthesis of such enol acetates was demonstrated by treating the acetylated
trichloromethylcarbinol 7 (Scheme 5) with CuCl/bpy (2 equiv each) in DCM under a nitrogen atmosphere. As expected, the
reaction occurred much faster than that of the simple trichloromethylcarbinol acetates observed earlier34 and proceeded to
completion in 1.5 h even at room temperature (20-25 ˚C). The acid chloride enol acetate 8 was isolated in 54% isolated yield.
Formation of a small amount of 2,2-dichlorovinyl phenyl ketone 9 was also observed. The stereochemistry of 8 was presumed on
the basis of our earlier observation.35
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Scheme 5. Surzur-Tanner Rearrangement of 7
Trichloromethylcarbinols are known to form dichloroepoxide in the presence of a base, which could be variously opened by
nucleophiles.1c Therefore, the Jocic-Reeve reaction of the amide 2l (Scheme 6) was performed with ethanolic KOH to furnish the
tartronamic acid derivative 10 in 62% isolated yield.
Scheme 6. Synthesis of Tartronamic Acid Derivative 10 from 2l
In conclusion, we have developed a general, direct and efficient route to the synthesis of trichloromethylcarbinols having a keto,
an ester or an amide functional group at the α-position from easily accessible α-halomethyl ketones, esters and amides,
respectively, in moderate to high yields. The present method is fairly general as variously substituted trichloromethylcarbinols were
successfully prepared. The applicability of the methodology for the synthesis of tert-trichloromethyl carbinols was also
demonstrated. These compounds may possess some interesting biological activities. Nitrates can also be prepared directly from
acetophenone derivatives.36 The products are potential synthetic intermediates. Synthetic applications of such
trichloromethylcarbinols for the preparation of chloromethyl-α-diketones, highly substituted trichloromethylated dihydrofurans and
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enol acetates of α-functionalized acid chlorides were demonstrated. The reaction of these compounds in the Jocic-Reeve reaction
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was also demonstrated.
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Experimental Section
General remarks
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IR spectra were recorded on FT-IR spectrometer by taking solid samples as KBr pellets and liquids as thin films on KBr discs. NMR
spectra were recorded on a 300 MHz FT NMR spectrometer in CDCl3 with TMS as internal standard. Multiplicities are indicated by the
following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet), m (multiplet), dd (doublet doublet), dt (doublet triplet),
td (triplet doublet). DEPT spectra were routinely recorded to identify different types of carbons. High-resolution mass spectra were
recorded on a mass spectrometer (ESI-TOF) in positive ion mode. Melting points were determined on an electrically heated apparatus by
taking the samples in a glass capillary sealed at one end and are uncorrected. The progress of the reaction was monitored by TLC. Iodine
was used for visualizing the spots. Almost all the compounds were purified using column chromatography. Silica gel (60−120 mesh) was
used as the stationary phase and n-hexane-EtOAc mixtures were used as the mobile phase. Solvents were evaporated on a rotary evaporator
under reduced pressure using an aspirator. Starting materials 1a-f were prepared by the bromination of the corresponding acetophenones.37
2-Iodoacetylfuran 1g and 1-iodo-2-octanone 1h were prepared from 2-chloroacetylfuran38 and 1-chloro-2-octanone,38 respectively. 1i was
commercially available and 1j-l were prepared by the bromoacetylation of amines using bromoacetylbromide in DCM at 0-25 ˚C.39
Synthesis of trichloromethylcarbinols
Typical procedure:
3,3,3-Trichloro-2-hydroxy-1-phenylpropan-1-one 2a: To a solution of 1a (2 mmol) in acetonitrile (10 mL) was added AgNO3 (0.340 g, 2
mmol) and stirred for 10 h at room temperature. Completion of the reaction was confirmed by TLC. DCM (50 mL) was then added and
stirred for additional 10 min. AgBr was precipitated out. The resulting solution was filtered and concentrated in vacuo to obtain the
corresponding nitrate in quantitative yield. Nitrate was taken in dry DMF (10 mL) and CCl3COONa (0.741 g, 4 mmol) was added in
portion over 5 min while maintaining the temperature at 23−25 ˚C. TLC was performed, which showed the disappearance of 1a after 30
min. The reaction mixture was diluted with EtOAc (80 mL) and washed with brine (2×50 mL). Organic layer was separated, dried (NaSO4)
and evaporated. The crude residue was purified by column chromatography (n-hexane−EtOAc, 9:1 v/v) to afford 3,3,3-trichloro-2-
1
hydroxy-1-phenylpropan-1-one 2a (0.381 g, 75%) as colorless flakes, mp 38 ˚C (n-hexane−EtOAc). H NMR (300 MHz, CDCl3): δ 8.02
(d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 5.63 (d, J = 9.9 Hz, 2H), 4.55 (d, J = 9.9 Hz, 1H, D2O exchangeable),
ppm; 13C NMR (75.5 MHz, CDCl3): δ 194.9 (C), 135.5 (C), 134.7 (CH), 129.6 (CH), 128.7 (CH), 98.0 (C), 79.5 (CH) ppm; IR (KBr): νmax
3421(s), 3066(m), 1678(s), 1594(m), 1448(m), 1397(s), 1281(m), 1183(s), 1112(m), 965(s), 821(s), 787(s), 749(s), 696(m), 579(m) cm-1;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H7Cl3O2Na 274.9404, found 274.9409.
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3,3,3-Trichloro-2-hydroxy-1-p-tolylpropan-1-one 2b: Colorless needles, mp 104 ˚C (n-hexane−EtOAc), 0.417 g, 78%; H NMR (300
MHz, CDCl3): δ 7.93 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 5.61 (d, J = 9.9 Hz, 1H), 4.61 (d, J = 9.9 Hz, 1H, D2O exchangeable),
2.45 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 194.2 (C), 146.1 (C), 132.8 (C), 129.8 (CH), 129.4 (CH), 98.1 (C), 79.2 (CH), 21.8
(CH3) ppm; IR (KBr): νmax 3440(m, br), 2974(m), 1671(s), 1599(m), 1513(m), 1462(m), 1315(s), 1270(m), 1177(s), 1110(m), 963(s),
821(s), 762(m), 686(m), 574(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H9Cl3O2Na 288.9560, found 288.9553.
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1
3,3,3-Trichloro-2-hydroxy-1-(4-methoxyphenyl)propan-1-one 2c: Colorless needles, mp 114 ˚C (n-hexane−EtOAc), 0.420 g, 74%; H
NMR (300 MHz, CDCl3): δ 8.04 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.58 (d, J = 9.9 Hz, 1H), 4.60 (d, J = 9.9 Hz, 1H, D2O
exchangeable), 2.45 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 192.6 (C), 164.9 (C), 132.3 (CH), 128.0 (C), 114.0 (CH), 98.4 (C), 79.0
(CH), 55.7 (CH3) ppm; IR (KBr): νmax 3310(m, br), 2970(m), 1669(s), 1602(m), 1424(m), 1288(s), 1225(m), 112(s), 1014(m), 818(s),
756(s), 719(s), 685(m), 584(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H9Cl3O3Na 304.9509, found 304.9513.
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1-(4-Bromophenyl)-3,3,3-trichloro-2-hydroxypropan-1-one 2d: Colorless flakes, mp 88 ˚C (n-hexane−EtOAc), 0.425 g, 64%; H NMR
(300 MHz, CDCl3): δ 7.89 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 5.57 (d, J = 9.9 Hz, 1H), 4.50 (d, J = 9.9 Hz, 1H, D2O
exchangeable) ppm; 13C NMR (75.5 MHz, CDCl3): δ 194.0 (C), 134.2 (C), 132.1 (CH), 130.9 (CH), 130.3 (C), 97.8 (C), 79.5 (CH) ppm;
IR (KBr): νmax 3337(m, br), 2984(m), 1679(s), 1583(m), 1420(m), 1287(m), 1229(m), 1119(s), 1070(m), 825(s), 772(m), 732(m), 682(m),
605(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H6BrCl3O2Na 352.8509, found 352.8508.
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3,3,3-Trichloro-2-hydroxy-1-(3-nitrophenyl)propan-1-one 2e: Colorless cubes, mp 116 ˚C (n-hexane−EtOAc), 0.358 g, 60%; H NMR
(300 MHz, CDCl3): δ 8.86 (s, 1H), 8.53 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.78 (t, J = 8.1 Hz, 1H), 5.65 (d, J = 10.2 Hz, 1H),
4.45 (d, J = 10.2 Hz, 1H, D2O exchangeable) ppm; 13C NMR (75.5 MHz, CDCl3): δ 193.3 (C), 148.3 (C), 136.8 (C), 134.8 (CH), 130.1
(CH), 128.6 (CH), 124.2 (CH), 97.4 (C), 80.0 (CH) ppm; IR (KBr): νmax 3429(m, br), 1690(s), 1530(m), 1350(s), 1277(m), 1126(s),
1089(m), 812(s), 703(m), 719(s), 588(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H6Cl3NO4Na 319.9255, found 319.9252.
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3,3,3-Trichloro-2-hydroxy-2-methyl-1-phenylpropan-1-one 2f: Colorless flakes, mp 60 ˚C (n-hexane−EtOAc), 0.321 g, 60%; H NMR
(300 MHz, CDCl3): δ 7.91 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.2 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 4.71 (s, 1H, D2O exchangeable), 2.10 (s,
3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 199.1 (C), 136.8 (C), 132.7 (CH), 129.6 (CH), 128.2 (CH), 103.4 (C), 87.6 (C), 22.5 (CH3)
ppm; IR (KBr): νmax 3425(m, br), 3060(m), 1679(s), 1593(m), 1446(m), 1386(s), 1251(m), 1170(s), 1096(m), 974(s), 826(s), 804(s),
778(s), 686(m), 619(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H9Cl3O2Na 288.9560, found 288.9552.
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3,3,3-Trichloro-1-(furan-2-yl)-2-hydroxypropan-1-one 2g: Colorless cubes, mp 108 ˚C (n-hexane−EtOAc), 0.292 g, 60%; H NMR (300
MHz, CDCl3): δ 7.76 (s, 1H), 7.49 (d, J = 3.9 Hz, 1H), 6.68 (dd, J = 3.9, 1.5 Hz, 1H), 5.43 (d, J = 10.5 Hz, 1H), 4.30 (d, J = 10.5 Hz, 1H,
D2O exchangeable) ppm; 13C NMR (75.5 MHz, CDCl3): δ 182.0 (C), 150.9 (C), 148.5 (CH), 121.4 (CH), 113.4 (CH), 98.1 (C), 79.9 (CH)
ppm; IR (KBr): νmax 3397(m, br), 3130(m), 1660(s), 1561(m), 1460(m), 1401(m), 1280(m), 1248(m), 1123(s), 1036(m), 872(m), 818(m),
767(s), 714(m), 586(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C7H5Cl3O3Na 264.9196, found 264.9201.
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1,1,1-Trichloro-2-hydroxynonan-3-one 2h: Colorless liquid, 0.251 g, 48%; 1H NMR (300 MHz, CDCl3): δ 4.68 (d, J = 7.8 Hz, 1H), 4.51
(d, J = 7.8 Hz, 1H, D2O exchangeable), 2.98 (dt, J = 15.0,7.8 Hz, 1H), 2.76 (dt, J = 15.0, 7.8 Hz, 1H), 1.69 (pent, J = 7.2 Hz, 2H), 1.37-
1.26 (m, 6H), 0.89 (t, J = 6.0 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 204.2 (C), 97.5 (C), 84.7 (CH), 42.5 (CH2), 31.5 (CH2), 28.6
(CH2), 23.7 (CH2), 22.4 (CH2), 14.0 (CH3) ppm; IR (KBr): νmax 3435(m, br), 2929(s), 2863(m), 1720(s), 1648(m), 1461(m), 1391(s),
1280(m), 1118(m), 1061(m), 820(s), 625(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H15Cl3O2Na 283.0030, found 283.0024.
Ethyl 3,3,3-trichloro-2-hydroxypropanoate 2i: Colorless flakes, mp 64 ˚C (n-hexane−EtOAc), 0.332 g, 75%; 1H NMR (300 MHz,
CDCl3): δ 4.65 (d, J = 9.3 Hz, 1H), 4.34-4.43 (m, 2H), 4.13 (d, J = 9.3 Hz, 1H, D2O exchangeable), 1.36 (t, J = 7.2 Hz, 3H) ppm; 13C
NMR (75.5 MHz, CDCl3): δ 167.9 (C), 97.8 (C), 80.9 (CH), 63.4 (CH2), 13.9 (CH3) ppm; IR (KBr): νmax 3374(m, br), 2994(m), 2938(m),
1735(s), 1472(m), 1393(s), 1302(s), 1217(s), 1128(m), 1014(s), 939(m), 862(s), 818(s), 720(s), 611(s) cm-1; HRMS (ESI-TOF): m/z [M +
Na]+calcd for C5H7Cl3O3Na 242.9353, found 242.9353.
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3,3,3-Trichloro-2-hydroxy-1-morpholinopropan-1-one 2j: Colorless cubes, mp 136 ˚C (n-hexane−EtOAc), 0.357 g, 68%; H NMR (300
MHz, CDCl3): δ 4.96 (d, J = 10.2 Hz, 1H), 4.57 (d, J = 10.2 Hz, 1H, D2O exchangeable), 3.63-3.80 (m, 4H) ppm; 13C NMR (75.5 MHz,
CDCl3): δ 165.8 (C), 99.2 (C), 75.7 (CH), 66.5 (CH2), 66.1 (CH2), 47.3 (CH2), 43.6 (CH2) ppm; IR (KBr): νmax 3226(m, br), 2971(m),
2858(m), 1631(s), 1474(m), 1427(m), 1233(m), 1110(s), 1051(m), 873(s), 781(m), 719(s), 627(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+
calcd for C7H10Cl3NO3Na 283.9618, found 283.9610.
3,3,3-Trichloro-2-hydroxy-N,N-diisopropylpropanamide 2k: Colorless flakes, mp 74 ˚C (n-hexane−EtOAc), 0.365 g, 66%; 1H NMR (300
MHz, CDCl3): δ 4.94 (d, J = 9.9 Hz, 1H), 4.71 (d, J = 9.9 Hz, 1H, D2O exchangeable), 4.39 (sept, J = 6.6 Hz, 1H), 3.57 (sept, J = 6.6 Hz,
1H), 1.46 (d, J = 6.6 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H), 1.26 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3): δ 165.7 (C), 99.4 (C), 76.4 (CH), 49.6 (CH), 47.1 (CH), 21.5 (CH3), 20.2 (CH3), 19.8 (CH3), 19.7 (CH3) ppm; IR (KBr): νmax
3365(s), 3001(m), 2971(m), 2936(m), 1644(s), 1475(m), 1417(m), 1351(m), 1296(s), 1109(m), 1040(m), 761(m), 707(s), 633(m) cm-1;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H16Cl3NO2Na 298.0139, found 298.0145.
3,3,3-Trichloro-2-hydroxy-N-methyl-N-phenylpropanamide 2l: Colorless needles, mp 126 ˚C (n-hexane−EtOAc), 0.367 g, 65%; 1H NMR
(300 MHz, CDCl3): δ 7.46 (dd, J = 8.1, 6.6 Hz, 2H), 7.41 (t, J = 6.9 Hz, 1H), 7.26 (d, J = 7.2 Hz, 2H), 4.78 (s, 1H), 4.23 (s, 1H, D2O
exchangeable), 3.39 (s, 3H), ppm; 13C NMR (75.5 MHz, CDCl3): δ 167.5 (C), 142.1 (C), 130.1 (CH), 128.5 (CH), 127.4 (CH), 99.0 (C),
76.2 (CH), 38.5 (CH3) ppm; IR (KBr): νmax 3304(s), 3057(m), 2928(m), 1666(s), 1592(m), 1494(m), 1384(s), 1290(m), 1101(s), 820(s),
770(m), 702(m), 648(m), 553(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H10Cl3NO2Na 303.9669, found 303.9674.
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3,3,3-Trichloro-2-hydroxy-2-(3-nitrophenyl)propyl nitrate 3: Colorless needles, mp 104 ˚C (n-hexane−EtOAc), 0.108 g, 18%; H NMR
(300 MHz, CDCl3): δ 8.64 (t, J = 1.8 Hz, 1H), 8.30-8.34 (m, 1H), 8.10 (dd, J = 7.8, 1.2 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 5.55 (d, J = 12.9
Hz, 1H), 5.39 (d, J = 12.9 Hz, 1H), 3.72 (s, 1H, D2O exchangeable) ppm; 13C NMR (75.5 MHz, CDCl3): δ 147.9 (C), 136.3 (C), 134.5
(CH), 129.0 (CH), 124.5 (CH), 123.9 (CH), 103.2 (C), 83.3 (C), 72.6 (CH2) ppm; IR (KBr): νmax 3458(s), 3094(m), 2919(m), 1647(s),
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1533(s), 1440(m), 1353(s), 1281(m), 1174(s), 1102(m), 1028(s), 834(s), 749(m), 672(s), 635(m), 587(m) cm-1; HRMS (ESI-TOF): m/z [M
+ Na]+ calcd for C9H7Cl3N2O6Na 366.9262, found 366.9263.
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1,1,1-Trichloro-3-(methyl(phenyl)amino)-3-oxopropan-2-yl 2-(methyl(phenyl)amino)-2-oxoacetate 4: The reaction of N-methyl-N-
phenylbromoacetamide 1l (0.456 g, 2 mmol) with AgNO3 (0.340 g, 2 mmol) in acetonitrile (10 mL) was stirred at room temperature (20-25
˚C) for 16 h. Chloroform (50 mL) was then added and the suspension was stirred for additional 10 min. The silver bromide thus
precipitated was filtered off and the filtrate was evaporated under reduced pressure to obtain the nitrate in quantitative yield.
The nitrate was dissolved in dry DMF (10 mL) and CCl3COONa (1.112 g, 6 mmol) was added to the solution portion-wise over a 5 min
duration with stirring at 20-25 ˚C. The reaction occurred vigorously with an increase in the temperature of the reaction mixture. The
stirring was continued for 90 min. The reaction mixture was then diluted with EtOAc (80 mL) and washed with brine (2×50 mL). The
organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure. The crude residue thus obtained was purified by column
chromatography (silica gel, n-hexane−EtOAc, 7:3 v/v) to afford 1,1,1-trichloro-3-{methyl(phenyl)amino}-3-oxopropan-2-yl 2-
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{methyl(phenyl)amino}-2-oxoacetate 4 (0.240 g, 54%) as colorless cubes, mp 146 ˚C (n-hexane−EtOAc). Colorless cubes, mp 146 ˚C (n-
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hexane−EtOAc), 0.240 g, 54%. H NMR (300 MHz, CDCl3) δ 7.29-7.43 (m, 8H), 7.04 (s, 2H), 5.71 (s, 1H), 3.36 (s, 3H), 3.26 (s, 3H)
ppm; 13C NMR (75.5 MHz, CDCl3) δ 161.3, 159.7, 159.6, 141.3, 140.4, 129.9, 129.8, 128.8, 128.7, 127.8, 127.3, 94.4, 74.0, 38.4, 36.3
ppm; IR (KBr) νmax 3064(m), 2983(m), 2937(m), 1770(s), 1682(s), 1589(m), 1493(m), 1458 (m), 1424(m), 1392(m), 1265(m), 1193(m),
1102(m), 1042(m), 912(m), 823(m), 786(m), 746(m), 664(m), 625(m), 559(m) cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H17Cl3N2O4Na 465.0146, found 465.0145.
Reaction of 3,3,3-Trichloro-2-hydroxy-N-methyl-N-phenylpropanamide 2l with 2 equivalents of sodium trichloroacetate:
A solution of the trichloromethylcarbinol 2l (0.565 g, 2 mmol) in dry DMF (10 mL) was added CCl3COONa (0.741 g, 4 mmol) portion-
wise over a 5 min duration with stirring at 20-25 ˚C. The reaction occurred vigorously with an increase in the temperature of the reaction
mixture. The stirring was continued for 60 min. The reaction mixture was diluted with EtOAc (80 mL) and washed with brine (2×50 mL).
The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure. The crude residue thus obtained was purified by
column chromatography (silica gel, n-hexane−EtOAc, 7:3 v/v) to afford 1,1,1-trichloro-3-{methyl(phenyl)amino}-3-oxopropan-2-yl 2-
{methyl(phenyl)amino}-2-oxoacetate 4 (0.275 g, 62%) as colorless cubes, mp 146 ˚C (n-hexane−EtOAc).
3-Chloro-1-phenylpropane-1,2-dione 5: An atmosphere of nitrogen gas was created by Schlenk technique in a flame dried 50 mL two-
neck round-bottomed flask equipped with a condenser, a rubber septum and a magnetic bar. Cuprous chloride (0.198 g, 2 mmol),
bipyridine (0.312 g, 2 mmol) and dry degassed DCE (20 mL) were added to the flask. The flask was again evacuated and filled with dry
nitrogen. The mixture was stirred for 15 min. While stirring, a solution of the ketocarbinol 2a (0.253 g, 1 mmol) in dry degassed DCE (5
mL) was slowly injected into the mixture during a period of 5 min. The resulting mixture was then heated at reflux for 1 h. Monitoring the
progress of the reaction by TLC indicated the disappearance of 2a after this time. The reaction mixture was cooled to room temperature
and n-hexane (25 mL) was added to it. The resulting mixture was stirred for 15 min under the open atmosphere and filtered. The filtrate
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was evaporated under reduced pressure. The crude product thus obtained was purified by flash column chromatography on a silica gel (60-
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120 mesh) column using n-hexane as the solvent for elution to obtain 3-chloro-1-phenylpropane-1,2-dione 5 (0.119 g, 65%) as a colorless
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liquid. H NMR (300 MHz, CDCl3): δ 8.05 (d, J = 7.5 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 4.65 (s, 1H) ppm; 13C
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NMR (75.5 MHz, CDCl3): δ 192.4 (C), 190.0 (C), 135.2 (C), 131.8 (CH), 130.4 (CH), 129.0 (CH), 45.6 (CH2) ppm; IR (KBr): νmax
3066(m), 2941(m), 1731(s), 1674(s), 1592(m), 1448(m), 1397(m), 1261(m), 1178(m), 1101(m), 951(m), 892(m), 761(m), 691(m), 642(m)
cm-1; HRMS (ESI-TOF): m/z [M + K]+ calcd for C9H7ClO2K 220.9772, found 220.9754.
Dimethyl 5-hydroxy-5-phenyl-4-(trichloromethyl)-4,5-dihydrofuran-2,3-dicarboxylate 6: A mixture of the ketocarbinol 2a (0.507 g, 2
mmol), DMAD (0.284 g, 2 mmol) and K2CO3 (0.276 g, 2 mmol)in THF (30 mL)was heated at reflux with stirring. The progress of the
reaction was monitored by TLC. After completion of the reaction (3 h), the volatiles were evaporated under reduced pressure. The residue
thus obtained was taken up in diethyl ether (80 mL) and filtered. The filtrate was washed with brine (3×20mL), dried (Na2SO4), filtered
and evaporated. The crude product thus obtained was recrystallized from a mixture of n-hexane and chloroform to obtain (Z)-dimethyl 5-
hydroxy-5-phenyl-4-(trichloromethyl)-4,5-dihydrofuran-2,3-dicarboxylate 6 (0.570 g, 72%) as colorless needles, mp 118 ˚C (n-
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hexane−chloroform). H NMR (300 MHz, CDCl3): δ 7.51 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 6.9 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 5.10 (s,
1H), 3.98 (s, 3H), 3.74 (s, 1H, D2O exchangeable), 3.65 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 162.9 (C), 159.4 (C), 153.8 (C),
143.5 (C), 128.8 (CH), 128.3 (CH), 125.0 (CH), 114.9 (C), 97.4 (CH), 94.1 (C), 84.7 (C), 53.3 (CH3), 52.2 (CH3) ppm; IR (KBr): νmax
3466(s), 3067(m), 2955(m), 1730(s), 1671(s), 1444(m), 1360(s), 1324(m), 1283(s), 1215(s), 1182(s), 1126(s), 1032(s), 1016(s), 932(s),
829(s), 788(m), 745(m), 692(m), 665(m), 532(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H13Cl3O6Na 416.9670, found
416.9681.
1,1,1-Trichloro-3-oxo-3-phenylpropan-2-yl acetate 7: In a 50 mL two-neck round-bottomed flask equipped with a calcium chloride guard
tube, a rubber septum and a magnetic bar were taken the ketocarbinol 2a (0.507 g, 2 mmol), pyridine (0.17mL, 2 mmol) and dry DCM (25
mL). The solution was cooled to 0 ˚C and stirred for 15 min. A solution of AcCl (0.15mL, 2 mmol) in DCM (5 mL) was then slowly
injected into the stirred solution over 5 min. The stirring was continued at 0-5 ˚C and the progress of the reaction was monitored by TLC,
which indicated that the reaction was complete in 1 h. The solution was diluted with DCM (50 mL) and washed with brine (2×50 mL). The
organic layer was dried (Na2SO4), filtered and evaporated. The crude product thus obtained was purified by column chromatography on
silica gel column using n-hexane−EtOAc (9:1 v/v), as the solvent for elution to obtain 1,1,1-trichloro-3-oxo-3-phenylpropan-2-yl acetate 7
(0.497 g, 84%) as a colorless liquid; 1H NMR (300 MHz, CDCl3): δ 8.06 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.2 Hz,
2H), 6.61 (s, 1H), 2.25 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 190.1 (C), 169.3 (C), 136.4 (C), 134.1 (CH), 129.0 (CH), 128.8 (CH),
94.1 (C), 77.9 (CH), 20.3 (CH3) ppm; IR (KBr): νmax 3065(m), 1758(s), 1700(s), 1596(m), 1448(s), 1373(m), 1281(m), 1223(s), 1082(s),
1006(m), 956(m), 798(s), 754(s), 685(s), 582(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H9Cl3O3Na 316.9509, found
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Dechlorinative Suzur-Tanner Rearrangement: Synthesis of (Z)-1-Chloro-3-oxo-3-phenylprop-1-enyl acetate 8 and 3,3-dichloro-1-
phenylprop-2-en-1-one 9: A flame dried 50 mL two-neck round-bottomed flask having a magnetic bar equipped with a condenser and
septum under nitrogen atmosphere purged with CuCl (0.198 g, 2 mmol) and bipyridine (0.312 g, 2 mmol) and dry DCM (20 mL) were
taken and stirred for 15 min to ensure the complex formation. Then 7 (0.295 g, 1 mmol) in dry DCM (5 mL) was injected to this solution
and stirred for 1.5 h. The reaction was completed as observed by TLC. n-Hexane (20 mL) was added and stirred for 15 min. Resulting
solution was filtered and reduced in vacuo. The crude was eluted with n-hexane by column chromatography to obtain 1-chloro-3-oxo-3-
phenylprop-1-enyl acetate 8 (0.122 g, 54%) as colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.5 Hz,
1H), 7.48 (t, J = 7.2 Hz, 2H), 6.83(s, 1H), 2.32 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 187.3, 167.6, 147.2, 136.0, 133.1, 129.3,
128.6, 124.7, 20.2 ppm; IR (KBr) νmax 3093(s), 1771(s), 1670(m), 1607(m), 1444(s), 1372(m), 1320(m), 1253(m), 1194(s), 1140(m),
1015(m), 971(s), 847(s), 708(s), 657(m) cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H9ClO3Na 247.0132, found 247.0129.
Further elution gave 3,3-dichloro-1-phenylprop-2-en-1-one40 9 (0.024 g, 12%) as colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J
= 7.2 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.27 (s, 1H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 186.7, 136.9, 135.5,
133.7, 128.8, 128.5, 124.0 ppm; IR (KBr) νmax 3059(m), 1671(s), 1568(s), 1449(m), 1265(m), 1221 (s), 1015(m), 938(m), 841(m), 788(m),
695(m), 628(m) cm-1.
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2-Ethoxy-3-(methyl(phenyl)amino)-3-oxopropanoic acid 10: A mixture of the trichloromethyl-hydroxyamide 2l (0.282 g, 1 mmol) and
KOH (0.280 g, 5 mmol) in ethanol (30 mL) was heated at reflux. The progress of the reaction was monitored by TLC, which indicated the
completion of the reaction after 2 h. The reaction mixture was cooled to room temperature and the ethanol was removed under reduced
pressure. The residual mass was taken up in EtOAc (50 mL) and washed successively with 2N HCl (50 mL) and brine (2×20 mL). The
organic layer was dried (Na2SO4), filtered and evaporated. The crude product thus obtained was purified by column chromatography on
silica gel (60-120 mesh) column using n-hexane−EtOAc (1:1 v/v) as the solvent for elution to obtain 2-ethoxy-3-{methyl(phenyl)amino}-
3-oxopropanoic acid 10 (0.147 g, 62%) as a colorless liquid. 1H NMR (300 MHz, CDCl3): δ 7.63 (s, 1H, D2O exchangeable), 7.41-7.21 (m,
5H), 4.36 (s, 1H), 3.33-3.44 (m, 1H), 3.25 (s, 3H), 3.10-3.21 (m, 1H), 1.03 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 169.7
(C), 166.7 (C), 142.2 (C), 129.7 (CH), 128.5 (CH), 127.4 (CH), 75.8 (CH), 66.3 (CH2), 38.0 (CH3), 14.7 (CH3) ppm; IR (KBr): νmax
3469(m, br), 2979(m), 2932(m), 2590(m), 1750(s), 1656(s), 1594(m), 1493(m), 1394 (m), 1292(m), 1216(m), 1120(m), 1033(m), 897(m),
773(m), 700(m), 669(m) cm-1; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H15NO4Na 260.0893, found 260.0893.
ASSOCIATED CONTENT
Supporting Information: Copies of 1H NMR and 13C NMR spectra of 2a-l, 3-10; ORTEP diagrams and CIFs of 4 and 6. This material is
available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
Current Address: Department of Chemistry, Indian Institute of Technology Jodhpur, Ratanada, Jodhpur-342011, India
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*soni.1@ iitj.ac.in
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful to the University Grant Commission, New Delhi, for a research fellowship to V.K.S.
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