First general route to substituted α-arylamino-α′ chloropropan-2-ones by oxidation of N-protected aminohalohydrins: The importance of disrupting hydrogen bond networks

Article abstract of DOI:10.1055/s-0030-1257938

The presence of a network of intra- and intermolecular hydrogen bonds in β-arylamino alcohols, confirmed by both IR spectroscopy and computer modeling, inhibits their oxidation to the corresponding α-amino ketones. A straightforward protocol, including highly regioselective protection (as carbamates) and subsequent oxidation with Dess-Martin periodinane, affords near quantitative yields of the desired N-protected ketones, which upon mild treatment with iodotrimethylsilane leads to a series of differently functionalized α-arylamino-α′-chloro ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1257938

PAPER
3545
First General Route to Substituted a-Arylamino-a¢-chloropropan-2-ones by
Oxidation of N-Protected Aminohalohydrins: The Importance of Disrupting
Hydrogen Bond Networks
S
ynthesis of Subst
i
itute
d
a
t
-
Aryla
t
a
o
¢
-chloroprop
r
an-2-one
i
s
o Pace,a Álvaro Cortés Cabrera,b María Fernández,a José V. Sinisterra,a,c Andrés R. Alcántara*a
a
Organic and Pharmaceutical Chemistry Department, Biotransformations Group, Faculty of Pharmacy,
Complutense University of Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: andresr@farm.ucm.es
b
c
Bioinformatics Unit, Center for Molecular Biology ‘Severo Ochoa’, C/Nicolás Cabrera 1, Autónoma University Campus, 28049 Madrid,
Spain
Industrial Biotransformations Service, Scientific Park of Madrid, C/Santiago Grisolía 2, 28760 Tres Cantos, Madrid, Spain
Received 8 June 2010
the desired amino ketone V. The singular reactivity of
such aminocarbonyl compounds is due to the presence of
the two reactive functions (amine and carbonyl) in vicinal
positions, and because of their opposite behavior (nucleo-
Abstract: The presence of a network of intra- and intermolecular
hydrogen bonds in b-arylamino alcohols, confirmed by both IR
spectroscopy and computer modeling, inhibits their oxidation to the
corresponding a-amino ketones. A straightforward protocol, in-
cluding highly regioselective protection (as carbamates) and subse- philic amine vs. electrophilic carbonyl), there can be ei-
quent oxidation with Dess–Martin periodinane, affords near
ther intra- or intermolecular condensations, so that the use
quantitative yields of the desired N-protected ketones, which upon
of protecting groups on both is frequently necessary in or-
mild treatment with iodotrimethylsilane leads to a series of differ-
der to circumvent this encumbrance.
ently functionalized a-arylamino-a¢-chloro ketones.
In addition, the functionalization of the a¢-position of the
Key words: amino alcohols, amino ketones, oxidation, protecting
ketone with a halogen complicates even more the reactiv-
ity of the structure, specially its synthesis.3 Nowadays,
structures presenting such motifs are gaining importance
because of their use in asymmetric syntheses of the central
core molecules of HIV protease inhibitors (e.g., indinavir,
Figure 1).4,5 As can be seen, the synthetic sequence de-
picted in Scheme 1 requires several steps, which may be
reduced to only one, by employing a different approach
based on the oxidation of readily available vicinal amino
alcohols6 (Scheme 2).
groups, hydrogen bonding
Compounds displaying both amino and carbonyl groups
are very useful building blocks, as this motif is recurrently
found in different fields of organic chemistry, such as al-
kaloid biosynthesis (e.g., morphine), synthesis of nitro-
gen-containing natural products [e.g., (+)-preussin], as
well as in heterocyclic (Friedländer chemistry) or medici-
nal chemistry.1,2
OH
OH
In particular, a-amino ketones provide prochiral precur-
sors for the industrial-scale synthesis of biologically ac-
tive compounds: adrenergic a1 agonists (adrenaline-
type), b2-selective agonists (anti-asthma drugs, e.g., sal-
butamol), b1-selective antagonists (e.g., metoprolol), or
broad spectrum antihelmintic drugs (levamisole)
(Figure 1).
H
H
HO
HO
N
N
HO
HO
(R)-adrenaline
(R)-salbutamol
N
S
N
Formally, the classical synthetic approach to a-amino ke-
tones (Scheme 1), involves the addition of an organome-
tallic reagent (organolithium compound or Grignard
reagents) to a suitable N-protected and activated amino
acid derivative (ester or Weinreb amide). However, this
standard procedure is complicated by the fact that the
starting amino acid I must be initially reduced to the cor-
responding primary alcohol II, which must be subse-
quently oxidized to the aldehyde III that undergoes
nucleophilic attack of the organometallic compound; fi-
nally, the obtained amino alcohol IV has to be oxidized to
HN
O
MeO
OH
(R)-metoprolol
(S)-levamisole
N
OH
OH
H
N
O
N
N
O
HN
SYNTHESIS 2010, No. 20, pp 3545–3555
Advanced online publication: 30.07.2010
x
x.
x
x
.
2
0
1
0
indinavir
DOI: 10.1055/s-0030-1257938; Art ID: P08610SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Drugs prepared from a-amino ketones

3546
V. Pace et al.
PAPER
NR1
a
b
2
NR1
NR1
2
2
R
N
OH
X
OH
[H]
[O]
O
OH
X
ArNHR
+
Ar
O
O
1a–g
I
II
III
R = H, Me
X = H, Cl
NR1
NR1
2
2
[O]
OH
O
R2M
a: amine (1.0 equiv), oxirane (1.0 equiv)
R2
R2
Zn(ClO4)⋅6H2O (2% mol), CHCl3, 50 °C, 4–24 h
b: amine (2.0 equiv), oxirane (1.0 equiv)
EtOH, reflux, 24 h
IV
V
R
1 = protecting group
1a (Ar = Ph, R = H, X = Cl) 87%, via a
Scheme 1 Classical synthetic route to a-amino ketones
1b (Ar = Ph, R = Me, X = Cl) 93%, via a
1c (Ar = 4-MeOC6H4, R = H, X = Cl) 78%, via b
1d (Ar = 4-O2NC6H4, R = H, X = Cl) 73%, via a
1e (Ar = 4-morpholino-3-FC6H3, R = H, X = Cl) 87%, via b
1f (Ar = 3,4-F2C6H3, R = H, X = Cl) 75%, via a
1g (Ar = Ph, R = H, X = H) 91%, via a
R
N
O
R
N
OH
[O]
X
X
Ar
Ar
Scheme 3 Preparation of starting b-arylamino alcohols 1 by oxirane
ring opening
1b' Ar = Ph, R = Me
1a Ar = Ph, R = H, X = Cl
1b Ar = Ph, R = Me, X = Cl
Scheme 2 Direct projected route to a-arylamino-a¢-halopropan-2-
ones starting from b-arylamino-b¢-halopropan-2-ols
with an N–CH3 to give alcohol 1b allowed easy oxidiza-
tion of the alcohol with Dess–Martin periodinane afford-
ing ketone 1b¢ in high yield (86%) (Scheme 2). It is worth
noting that the unsuccessful oxidation of the N-unprotect-
ed amino alcohols seems not to be a consequence of the
known incompatibility between amino functions and oxi-
dants, but rather it could be caused by the presence of a
strong hydrogen bond network existing in such structures.
In fact, the simple addition of salts (ZnBr2, MgBr2, CeCl3)
to the amino alcohol solution prior to the oxidant did not
modify the observed pattern.
This technique, to the best of our knowledge, has been
only applied to those amino alcohols bearing the nitrogen
atom substituted with protecting groups such as phthal-
imido,7 Cbz,8 or N,N-dibenzyl.9 Interestingly, the Swern
oxidation, successfully employed for the preparation of
tertiary amino ketones,10 was not applicable to these struc-
tures presenting a secondary arylamino function possess-
ing a free NH.11 As part of our effort in synthesizing a-
arylamino-a¢-chloropropan-2-ones,3 we have devised a
new route to obtain such compounds, starting from vicinal
halohydrins generated by the ring opening of commercial-
ly available epichlorohydrin.
This result, as well as the literature precedents confirming
the feasible oxidation of isosteric phenoxy alcohols,14–16
prompted us to verify the existence of the above-men-
tioned strong network of hydrogen bonds in the amino al-
cohols, which could be hindering their oxidation. To
confirm this fact, IR spectroscopy as well theoretical stud-
ies (based on the evaluation of the energies for intra- and
intermolecular hydrogen bonds by molecular dynamics)
were performed. As model compounds, we selected alco-
hols 1a and 1b due to the completely distinct experimental
behavior observed upon oxidation.
In this sense, 1-chloro-3-(phenylamino)propan-2-ol (1a)
was chosen as model substrate, since it possesses both
functionalities (arylamino and halo moieties) required for
our target compounds.
Thus, b-arylamino alcohols were prepared in high yield
(>85%) by employing two different synthetic protocols
(Scheme 3): opening of epoxides by anilines catalyzed by
hexahydrated zinc(II) perchlorate12 (via route a), as well
the uncatalyzed, direct ring opening in refluxing ethanol13
(via route b).
After parameterization and subsequent validation of the
parameters (see Experimental Part), the analysis of the
MD simulations and quantum chemistry calculations al-
lowed the thermodynamic properties of the hypothesized
hydrogen bonds existing between molecules to be esti-
mated. For alcohol 1a, having a free N–H, the hydrogen
bond energy is described by two different terms referring
to the intermolecular (3.04 kcal/mol) and intramolecular
(1.30 kcal/mol) contributions, respectively. On the other
hand, for alcohol 1b, only the intermolecular hydrogen
bond contribution (0.89 kcal/mol, lower than the corre-
sponding term calculated for alcohol 1a) can be estimated.
Thus, visual inspection of the trajectories allowed a deter-
mination that alcohol 1a forms aggregates of molecules,
linked by a network of hydrogen bonds existing between
the amino and the hydroxy moieties of different mole-
Nevertheless, the subsequent oxidation of the amino alco-
hols did not proceed along the projected route, since all at-
tempts to oxidize alcohol 1a by employing different
oxidizing agents (PCC, PFC, Jones, Swern, TPAP–NMO,
Dess–Martin periodinane), as well different reaction con-
ditions (temperature, solvents, stoichiometric ratios) gave
either the unaltered starting material or an inseparable
mixture of many compounds, which did not show any
1
trace of the target structures, as indicated by H NMR
spectra of the crude reaction mixture. This pattern was ob-
served independently of the electronic nature of the sub-
stituent on the aromatic ring (4-methoxyphenyl, 4-
nitrophenyl). However, the replacement of the free N–H
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PAPER
Synthesis of Substituted a-Arylamino-a¢-chloropropan-2-ones
3547
amino alcohols, the agreement between the experimental
observed oxidation and the dynamics simulation was con-
firmed.
In order confirm the existence of the hypothesized hydro-
gen bonds, we decided to perform a study based on an ex-
perimental approach. Thus, IR spectra of model
compounds 1a and 1b were recorded at progressively
lower concentrations of the sample, in order to evaluate
the behavior of a molecule of the compound ideally in the
absence of any other similar molecules in its proximity.
For 1b, as displayed in Figure 3, the spectrum recorded in
dichloromethane (0.1 M) shows a broad shape peak for
the hydroxy function at 3421 cm–1, which is symptomatic
of the presence of an intermolecular hydrogen bond; by
diluting the sample concentration (0.025 M), we noted a
narrower peak jointly with a hypsochromic effect on the
absorption wave number (3581 cm–1). This last fact can be
attributed to the disappearance of the intermolecular inter-
actions and, therefore, the hydrogen bonds. The same IR
analysis for compound 1a (Figure 4) revealed the pres-
ence of strong both inter- and intramolecular hydrogen
bonds, as deduced from the broad peak that refers to the
same OH, which does not suffer any shape modification,
since it appears as a broad shape also at lower concentra-
tions (0.025 M). The displacement of the wave number
from 3393 cm–1 (0.1 M) to 3591 cm–1 (Figure 4) may be
understood as a consequence of the rupture of the inter-
molecular hydrogen bonds, while maintaining the typical
broad shape appears to be symptomatic of the continuous
presence of the intramolecular hydrogen bonds.
Figure 2 Hydrogen bond networks in the simulation of compound
1a showing hydrogen bond distances (left) and simulation of com-
pound 1b (right)
cules, as can be seen from the distances between those at-
oms depicted in Figure 2. Significantly, this theoretical
result supported the fact that this compound is solid at
room temperature (mp 38–39 °C).17 In contrast, the pres-
ence of a methyl group in compound 1b prevents such
kind of interactions and, therefore, avoids the formation of
the aforementioned aggregates (Figure 2). As a conse-
quence, alcohol 1b shows a lower transition temperature,
thus it is liquid at room temperature.18 Thus, we may at-
tribute the real cause of the impossibility to perform the
oxidation of our amino alcohols to the presence of this
network of widely diffused hydrogen bonds existing in the
case of a secondary amine function. Because of the ab-
sence of such hydrogen bond networks in the N-protected
Figure 3 IR spectrum of compound 1b recorded in CH2Cl2 at 0.1 M (red line) and at 0.025 M (purple line)
Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York

3548
V. Pace et al.
PAPER
Figure 4 IR spectrum of compound 1a recorded in CH2Cl2 at 0.1 M (black line) and at 0.025 M (green line)
The major consequence of this hydrogen bond network, dative hydrolysis3 of vinyl halides,19 we described the pro-
demonstrated by both theoretical and IR studies for com- tection of the aniline nitrogen with a trifluoroacetamide,
pound 1a, is the impossibility to perform the oxidation, leading to excellent results due to its easy introduction and
supporting our experimental data.
removal. Unfortunately, any attempt to selectively protect
the nitrogen without affecting the hydroxy function using
a literature protocol,20 led to the recovery of only the N,O-
diprotected compound 2 (Scheme 4), which after aqueous
workup to remove the trifluoroacetic ester, afforded the
starting alcohol 1a. Analogously, prior protection of the
Thus, the main requirement for the successful oxidation of
b-arylamino alcohols (absence of intramolecular hydro-
gen bonds), can be fulfilled by simply protecting the ami-
no moiety with an adequate group. In our previous work
concerning the synthesis of such compounds via the oxi-
O
F3C
O
O
CF3
Cl
N
TFAA (1.1 equiv)
DIPEA, THF, –78 °C to 0 °C
30 min, 63%
2
H2O
OH
H
OH
H
N
N
Cl
Cl
1a
1a
ImSiMe3, CH2Cl2
0 °C, 30 min, quant.
TFAA (0.95 equiv)
DIPEA, THF, –78 °C
10 min, 81%
OTMS
H
N
Cl
3
Scheme 4 Failed N-regioselective trifluoroacetylation of alcohol 1a
Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted a-Arylamino-a¢-chloropropan-2-ones
Table 1 Amino Alcohols 4–6 Protected as Moc, Cbz, or Boc
3549
alcohol as TMS ether 3, followed by trifluoroacetylation,
also led to the starting alcohol 1a, probably because of mi-
gration of the trifluoroacetyl group from the nitrogen to
the oxygen of the labile TMS ether.21
Carbamates
Entry Amino R1
alcohol
PG,
Product Isolated
OCOR2
yield (%)
As a consequence of the impossibility to employ N-triflu-
oroacetamide protection, the alternative use of carbamates
was evaluated. Thus, a series of differently N-protected
amino alcohols was prepared (Scheme 5 and Table 1). For
Boc protection, complete chemoselectivity on the nitro-
gen atom was observed, with no traces of O-acylation, by
heating di-tert-butyl dicarbonate in ethanol, as reported by
Vilaivan;22 thus, Boc-amino alcohols were obtained in
high to very high yields, depending on the relative nucleo-
philicity of the amine. In contrast, using methyl chlorofor-
mate for methoxycarbonyl (Moc) protection, according to
a standard procedure (K2CO3, reflux, 12 h23 or CH2Cl2, 0
°C24), gave a 1:1 mixture of N-protected and N,O-dipro-
tected compounds, as noted from the crude proton spec-
trum. To avoid tedious chromatographic separation, a
straightforward protocol for highly selective nitrogen pro-
tection of the amine in the presence of an excess of acylat-
ing agent, leading to excellent yields in short reaction
times, was designed, via the in situ hydrolysis of the car-
bonate under strongly basic conditions. In fact, GC-MS
analysis revealed a small amount (<10%) of N,O-dipro-
tected product at the beginning of the reaction, which
completely disappeared after about 30 minutes. To the
best of our knowledge, this is the first report of a one-step
nitrogen protection and oxygen deprotection. Remark-
ably, because of the high concentration of acylating agent
in the reaction medium, the electronic effect of the aro-
matic substituent did not influence the reactivity. It is
worth mentioning that this technique may be successfully
applied also in the case of Cbz protection, even if com-
pound 6a (Table 1, entry 3) was obtained in lower yield,
presumably due to steric hindrance.
1
2
3
4
5
6
7
8
1a
1a
1a
1c
1d
1e
1f
H
Boc
Moc
Cbz
Moc
Boc
4aa
5a
6a
5c
74
H
95
H
87
4-OMe
4-NO2
91
4da
5e
65
4-morpholino-3-F Moc
100
94
3,4-F2
H
Moc
Boc
5f
1g
4gb
89
a X = Cl.
b X = H.
With these optimized conditions in hand, the oxidation of
the N-protected amino alcohols 4–6 using Dess–Martin
periodinane was performed (Scheme 6, Table 2). As can
be seen, all reactions went to completion within 30 min-
utes with excellent recovered yields (>90%). The nature
of the carbamate protecting group affected neither the ox-
idation rate nor the conversion. Thus, these data confirm
our initial hypothesis concerning the hydrogen bonding
effect: all N-protected compounds were easy oxidized,
and in this way structures 7–14 are described herein for
the first time.
OR2
OR2
O
O
OH
O
DMP (1.2 equiv)
N
X
N
X
CH2Cl2, 30 min
90–100%
R1
7–14
4–6
R1
OH
H
R2 = Me, t-Bu, Bn
X = H, Cl
N
X
R1
Scheme 6 Dess–Martin periodinane promoted oxidation of N-carb-
amate protected b-arylamino alcohols
1a–g
ClCO2R2 (10 equiv)
K2CO3 (10 equiv)
MeOH–H2O (1:1)
0 °C, 30 min to 2 h
87–100%
X = H, Cl
Boc2O (1.0 equiv)
EtOH, r.t. to 50 °C
24 h, 65–89%
Thus, this synthetic protocol shows a wide applicability,
since no limitations derived from either electron-donor or
electron-withdrawing nature of the aromatic substituent
were observed, while the oxidative hydrolysis of vinyl ha-
lides was not possible for anilines bearing an electron-
donor group.
t-BuO
O
OR2
O
OH
OH
N
X
N
Cl
The last step for the proposed methodology leading to the
synthesis of a-arylamino-a¢-chloropropanones requires
the removal of the amino-protecting groups (Scheme 7,
Table 3). As shown previously, the use of acidic condi-
tions to remove the Boc group from ketone 8 resulted in
chlorine migration.3 For this reason, we considered as a
useful alternative the iodotrimethylsilane-promoted
cleavage25 at low temperature (–20 °C to 0 °C), just to
R1
4a,d X = Cl
4g X = H
R1
5a,c,e,f R2 = Me
6a R2 = Bn
Scheme 5 N-Regioselective protection of b-amino alcohols
Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York

3550
V. Pace et al.
PAPER
Table 2 Dess–Martin Periodinane Oxidation of N-Carbamate Protected b-Amino Alcohols
Entry
b-PG-Amino alcohol R1
X
PG, OCOR2
Boc
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
4a
5a
6a
5c
4d
5e
5f
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
7
8
100
95
92
90
98
97
99
94
H
Moc
H
Cbz
9
4-OMe
Moc
10
11
12
13
14
4-NO2
Boc
4-morpholino-3-F
Moc
3,4-F2
H
Moc
4g
Boc
Table 3 TMSI-Promoted Cleavage of N-Carbamates
Entry
N-Carbamate R1
X
OCOR2
a-Amino ketone Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
7
8
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Boc
Moc
Cbz
Moc
Boc
Moc
Moc
Boc
15
15
15
16
17
18
19
20
3
4
74
76
80
71
83
75
81
79
H
9
H
16
24
2
10
11
12
13
14
4-OMe
4-NO2
4-morpholino-3-F
24
16
3
3,4-F2
H
avoid competing silyl enol ether formation observed with chloropropanones, regardless of the substitution on the
analogous reagents.26 In fact, deprotection of a-Boc-ami- aromatic moiety, is described; in particular, through this
no ketones 7, 11, and 14 proceeded smoothly and reached methodology, several not previously described a-arylami-
completion in only three hours. On the other hand, cleav- no ketones bearing strong electron-donor groups were
age of Moc urethanes 8, 10, 12, and 13 required 24 hours synthesized. A plausible spectroscopic and quantum
to recover satisfactory yields ranging from 71% to 83% of chemistry explanation is postulated to understand the
the desired unprotected ketones. This mild cleavage was mandatory presence of amino protecting groups, since in
feasible due to the enhanced Lewis basicity of the carbo- the presence of free aromatic amines, a strong intramolec-
nyl group in the carbamate moiety, as a corollary of the ular hydrogen bonds hinders the oxidation. Finally, by us-
delocalization of the nitrogen lone pair into the p-system ing an easy chemoselective procedure, the deprotection of
of the aniline. As a clear consequence, compounds 11 and different carbamates allowed the synthesis of a-arylami-
13 (entries 5 and 7), bearing an electron-withdrawing no-a¢-chloropropanones in high yields.
group, gave the highest yields.
All 1H, 13C, and 19F NMR were recorded on a Bruker AC-250 spec-
OR2
trometer at 250 MHz, 62.5 MHz, and 235 MHz, respectively, using
a convenient deuterated solvent with the residual peak as internal
standard in the case of CDCl3. Carbon multiplicities were obtained
from DEPT experiments. All melting points are uncorrected. IR ab-
sorption spectra were recorded on a Shimadzu FT-IR 8400S
(E41107) spectrophotometer at the Industrial Biotransformations
Service of the Madrid Scientific Park. Spectra analyses were per-
formed with the software Shimadzu IRsolution (Version 1.21,
2005). Elementary microanalyses were carried out in the corre-
sponding ‘Centro de Apoyo a la Investigación’ of the Complutense
University, Madrid, using a Leco® CHNS 932 equipment. Column
chromatography purifications used silica gel 60 (40–63 mm). Melt-
ing points are uncorrected. Solns were evaporated under reduced
pressure with a rotary evaporator and the residue was column chro-
O
O
O
H
N
X
TMSI (1.0 equiv)
N
X
CH2Cl2, –20 °C to 0 °C
3–24 h, 71–83%
15–20
R1
7–14
R1
R
2 = Me, t-Bu, Bn
X = H, Cl
Scheme 7 N-Selective carbamate removal by employing TMSI
In this paper, a widely applicable and efficient protocol
for the synthesis of an interesting class of a-arylamino-a¢-
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PAPER
Synthesis of Substituted a-Arylamino-a¢-chloropropan-2-ones
3551
matographed (silica gel, EtOAc–hexanes mixtures unless otherwise
specified). TLC was carried out on aluminum sheets precoated with
silica gel 60F254 (Macherey-Nagel, Merck); the spots were visual-
ized under UV light (l = 254 nm) and/or with aq KMnO4. All chem-
icals were purchased from Sigma Aldrich and solvents were
purified by distillation immediately before use according standard
procedures. Compounds 1a,18 1b,18 1c,18 1d,13 and 1g27 were synthe-
sized as previously described. Compounds 15,3 17,3 and 2028
showed spectroscopic and physicochemical properties identical to
those reported. Epoxide ring openings catalyzed by Zn(ClO4)2·6 H2O
(via route a)12 and by refluxing in EtOH (via route b)29 were per-
formed according literature procedures.
was stirred for 15 min. The organic phase was separated, dried
(Na2SO4), and concentrated.
1-Chloro-3-[methyl(phenyl)amino]propan-2-one (1b¢)
Following the general procedure using 1-chloro-3-[methyl(phe-
nyl)amino]propan-2-ol (1b, 299 mg, 1.50 mmol) and DMP (763
mg, 1.80 mmol, 1.50 equiv), column chromatography (silica gel,
hexanes–EtOAc, 4:1) gave 1b¢ (255 mg, 86%); mp 59 °C.
IR (NaCl): 3082, 1743 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.08 (s, 3 H), 4.16 (s, 2 H), 4.24
(s, 2 H), 6.64 (d, J = 8.2 Hz, 2 H), 6.79 (t, J = 7.1 Hz, 1 H), 7.25 (dd,
J = 7.1, 8.2 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 40.03, 46.77, 61.00, 112.26,
1-Chloro-3-[(3-fluoro-4-morpholinophenyl)amino]propan-2-ol
(1e)
117.62, 129.50, 148.54, 202.33.
A mixture of 3-fluoro-4-morpholinoaniline30 (981 mg, 5.00 mmol)
and epichlorohydrin (231 mg, 2.50 mmol) was stirred under reflux
in EtOH (10 mL) for 24 h. The mixture was cooled to r.t. and con-
centrated in vacuo. The residue was separated by column chroma-
tography (silica gel, EtOAc–hexanes, 1:1) to give 1e (628 mg, 87%)
as an oil.
Anal. Calcd for C10H12ClNO: C, 60.76; H, 6.12; N, 7.09. Found: C,
60.85; H, 6.25; N, 7.21.
1-Chloro-3-(2,2,2-trifluoro-N-phenylacetamido)propan-2-yl
2,2,2-Trifluoroacetate (2)
Amino alcohol 1a (186 mg, 1.00 mmol) was dissolved in anhyd
THF (5 mL) and the reaction was cooled to –78 °C. DIPEA (0.19
mL, 1.10 mmol) was added and the reaction was stirred for 5 min.
TFAA (0.15 mL, 1.10 mmol) was then added dropwise over 10 min,
and the temperature was allowed to reach 0 °C. The solvent was
evaporated to dryness and the crude residue was purified by column
chromatography (silica gel, hexanes–EtOAc, 9.5:0.5) to give 2 (238
mg, 63%) as a colorless oil.
IR (NaCl): 3265, 1640, 1523, 1458, 1120 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.23 (dd, J = 7.7, 13.1 Hz, 1 H),
3.36 (dd, J = 4.0, 13.1 Hz, 1 H), 3.65 (dd, J = 4.0, 13.1 Hz, 2 H),
3.78 (dd, J = 4.5, 9.2 Hz, 4 H), 4.11 (m, 1 H), 4.26 (m, 4 H), 6.45
(m, 2 H), 6.82 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 47.40, 47.56, 51.75, 67.15,
69.76, 103.90 (d, 2JC,F = 26.1 Hz), 110.69 (d, 4JC,F = 4.0 Hz), 120.28
(d, 4JC,F = 4.1 Hz), 131.52 (d, 3JC,F = 9.5 Hz), 144.51 (d, 3JC,F = 10.6
Hz), 156.84 (d, 1JC,F = 245.0 Hz).
IR (NaCl): 1791, 1698, 1597, 1496, 1219, 1153, 1028, 915, 700 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.64 (dd, J = 5.7, 12.5 Hz, 1 H),
3.74 (dd, J = 4.3, 12.5 Hz, 1 H), 4.04 (dd, J = 3.7, 14.5 Hz, 1 H),
4.13 (dd, J = 7.3, 14.5 Hz, 1 H), 5.56 (m, 1 H), 7.28 (m, 2 H), 7.50
(m, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 41.53, 52.19, 73.66, 113.41 (d,
1JC,F = 277 Hz), 115.29 (d, 1JC,F = 298 Hz), 126.70, 128.68, 128.84,
129.38, 155.77 (d, 2JC,F = 43 Hz), 156.85 (d, 2JC,F = 37 Hz).
19F NMR (235 MHz, CDCl3): d = –164.42 (br s).
Anal. Calcd for C13H18ClFN2O2: C, 54.07; H, 6.28; N, 9.70. Found:
C, 54.15; H, 6.36; N, 9.75.
1-Chloro-3-[(3,4-difluorophenyl)amino]propan-2-ol (1f)
The mixture of 3,4-difluoroaniline (594 mg, 6.00 mmol) and epi-
chlorohydrin (556 mg, 6.00 mmol) in the presence Zn(ClO4)2·6 H2O
(22 mg, 2 mol%) in CHCl3 (15 mL) at 50 °C was stirred for 24 h.
The mixture was cooled to r.t., washed with H2O (10 mL), and ex-
tracted with CH2Cl2 (2 × 15 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was separated by column chromatography (silica gel, EtOAc–
hexanes, 1:4) to give 1f (997 mg, 75%) as a colorless oil.
19F NMR (235 MHz, CDCl3): d = –67.6 (br s), –75.25 (br s).
Anal. Calcd for C13H10ClF6NO3: C, 41.34; H, 2.67; N, 3.71. Found:
C, 41.44; H, 2.56; N, 3.63.
N-[3-Chloro-2-(trimethylsilyloxy)propyl]aniline (3)
Amino alcohol 1a (215 mg, 1.16 mmol) was dissolved in CH2Cl2 (5
mL) under N2. The soln was cooled to 0 °C, then N-(trimethylsi-
lyl)imidazole (0.17 mL, 1.19 mmol) was added dropwise. The mix-
ture was stirred at 0 °C for 30 min, washed with H2O (5 mL), and
extracted with CH2Cl2 (2 × 15 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated in vacuo to give 3
(299 mg, quant.) as a colorless oil that did not require further puri-
fication.
IR (NaCl): 3257, 1632 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.18 (dd, J = 7.2, 13.0 Hz, 1 H),
3.36 (dd, J = 4.2, 13.0 Hz, 3 H), 3.61–3.74 (m, 2 H), 4.08 (m, 1 H),
6.35 (m, 1 H), 6.48 (m, 1 H), 7.01 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 47.91, 47.97, 51.75, 70.15,
2
4
4
102.47 (d, JC,F = 20.7 Hz), 108.99 (dd, JC,F = 3.1 Hz, JC,F = 5.5
4
2
IR (NaCl): 3410, 2957, 1603, 1505, 1434, 1315, 1253, 1099, 1076,
843, 750, 692 cm–1.
Hz), 118.02 (dd, JC,F = 1.9 Hz, JC,F = 17.3 Hz), 143.87 (dd,
3JC,F = 14.7 Hz, JC,F = 236.0 Hz), 145.09 (dd, JC,F = 1.9 Hz,
1
4
3JC,F = 8.5 Hz), 151.26 (dd, 3JC,F = 14.7 Hz, 1JC,F = 243.0 Hz).
1H NMR (250 MHz, CDCl3): d = 0.21 (s, 9 H), 3.26 (dd, J = 5.9,
13.1 Hz, 1 H), 3.42 (dd, J = 4.3, 13.1 Hz, 1 H), 3.57 (dd, J = 5.9,
10.9 Hz, 1 H), 3.61 (dd, J = 6.0, 10.9 Hz, 1 H), 4.06 (br s, 1 H), 4.11
(m, 1 H), 6.69 (dd, J = 0.9, 8.6 Hz, 2 H), 6.78 (t, J = 7.3 Hz, 1 H),
7.24 (dd, J = 7.3, 8.6 Hz, 2 H).
19F NMR (235 MHz, CDCl3): d = –164.42 (br s).
Anal. Calcd for C9H10ClF2NO: C, 48.77; H, 4.55; N, 6.32. Found:
C, 48.54; H, 4.61; N, 6.26.
13C NMR (62.5 MHz, CDCl3): d = 3.02, 46.72, 47.36, 71.45,
113.54, 118.19, 129.78, 148.30.
Secondary Alcohol Oxidation with Dess–Martin Periodinane
(DMP); General Procedure
To a soln of alcohol (1.00 equiv) in CH2Cl2 (10 mL) at r.t., DMP
(1.20 equiv) was added and the mixture was stirred at the same tem-
perature for 30 min. Et2O (20 mL) and aq 1% Na2S2O3 soln (5 mL)
were added followed by sat. NaHCO3 soln and the resulting mixture
Anal. Calcd for C12H20ClNOSi: C, 55.90; H, 7.82; N, 5.43. Found:
C, 55.78; H, 7.94; N, 5.30.
Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York

3552
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PAPER
N-Boc Protection of Amino Alcohols; General Procedure22
To a soln of the amino alcohol (1.00 mmol) in EtOH (5 mL) was
added Boc2O (1.00 mmol).The reaction was stirred at 50 °C for 24
h, the solvent was removed in vacuo, and the crude product was pu-
rified as indicated below.
IR (NaCl): 3423, 3086, 1768, 1606 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.52 (dd, J = 5.4, 11.1 Hz, 2 H),
3.59 (dd, J = 5.4, 11.1 Hz, 2 H), 3.67 (s, 3 H), 3.75 (br s, 1 H), 4.05
(m, 1 H), 7.26–7.40 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 47.18, 53.35, 54.36, 70.23,
127.22, 128.32, 129.24, 141.90, 157.48.
tert-Butyl 3-Chloro-2-hydroxypropyl(phenyl)carbamate (4a)
Following the general procedure using 1a (186 mg, 1.00 mmol) and
Boc2O (218 mg, 1.00 mmol); column chromatography (silica gel,
hexanes–EtOAc, 4:1) gave 4a (211 mg, 74%) as a colorless oil.
Anal. Calcd for C11H14ClNO3: C, 54.22; H, 5.79; N, 5.75. Found: C,
54.35; H, 5.85, N, 5.63.
IR (NaCl): 3265, 1640, 1523, 1458, 1120 cm–1.
Benzyl 3-Chloro-2-hydroxypropyl(phenyl)carbamate (6a)
Following the general procedure using 1a (186 mg, 1.00 mmol) and
benzyl chloroformate (1706 mg, 10.00 mmol); column chromatog-
raphy (silica gel, hexanes–EtOAc, 9:1) gave 6a (269 mg, 87%) as a
colorless solid; mp 63 °C.
1H NMR (250 MHz, CDCl3): d = 1.47 (s, 9 H), 3.24 (dd, J = 7.2,
13.2 Hz, 1 H), 3.40 (dd, J = 4.2, 13.2 Hz, 1 H), 3.61 (m, 2 H), 4.09
(m, 1 H), 7.20–7.35 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 28.62, 47.49, 54.42, 71.25,
81.73, 127.00, 127.40, 129.38, 143.03, 156.44.
IR (NaCl): 3435, 3081, 1759, 1600, 1435, 988 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.25 (dd, J = 5.9, 13.1 Hz, 1 H),
3.42 (dd J = 4.3, 13.1 Hz, 1 H), 3.56 (m, 2 H), 4.08 (m, 1 H), 5.21
(s, 2 H), 6.67–6.79 (m, 3 H), 7.19–7.25 (m, 2 H), 7.38–7.42 (m, 5
H).
13C NMR (62.5 MHz, CDCl3): d = 46.05, 46.74, 69.55, 70.80,
112.93, 117.59, 128.16, 128.36, 128.40, 129.13, 134.95, 147.61,
157.13.
Anal. Calcd for C14H20ClNO3: C, 58.84; H, 7.05; N, 4.90. Found: C,
58.94; H, 7.17; N, 4.73.
tert-Butyl 3-Chloro-2-hydroxypropyl(4-nitrophenyl)carbamate
(4d)
Following the general procedure using 1d (180 mg, 0.78 mmol) and
Boc2O (170 mg, 0.78 mmol); column chromatography (silica gel,
hexanes–EtOAc, 4:1) gave 4d (168 mg, 65%) as a yellow oil.
Anal. Calcd for C17H18ClNO3: C, 63.85; H, 5.67; N, 4.38. Found: C,
63.98; H, 5.80; N, 4.49.
IR (NaCl): 3382, 2982, 1766, 1601, 1532, 1504, 1470, 1309, 1187,
1114, 1078, 999 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.48 (s, 9 H), 3.27 (dd, J = 7.7,
13.7 Hz, 1 H), 3.48 (dd, J = 5.1, 13.7 Hz, 1 H), 3.63 (m, 2 H), 4.05
(m, 1 H), 6.57 (dd, J = 2.1, 9.2 Hz, 2 H), 8.03 (dd, J = 2.1, 9.2 Hz,
2 H).
Methyl 3-Chloro-2-hydroxypropyl(4-methoxyphenyl)carbam-
ate (5c)
Following the general procedure using 1c (216 mg, 1.00 mmol) and
methyl chloroformate (945 mg, 10.00 mmol); column chromatogra-
phy (silica gel, hexanes–EtOAc, 7:3) gave 5c (248 mg, 91%) as a
colorless oil.
13C NMR (62.5 MHz, CDCl3): d = 27.82, 46.49, 47.53, 70.06,
85.82, 111.85, 126.89, 138.57, 147.35, 153.70.
IR (NaCl): 3360, 3081, 1770, 1464, 1237, 1180, 1027, 824 cm–1.
Anal. Calcd for C14H19ClN2O5: C, 50.84; H, 5.79; N, 8.47. Found:
C, 50.98; H, 5.66; N, 8.59.
1H NMR (250 MHz, CDCl3): d = 3.20 (dd, J = 5.9, 12.9 Hz, 1 H),
3.36 (dd, J = 4.2, 12.9 Hz, 1 H), 3.63–3.73 (m, 2 H), 3.68 (s, 3 H),
3.78 (s, 3 H), 4.09 (m, 1 H), 6.64 (dd, J = 1.5, 7.4 Hz, 2 H), 6.82 (dd,
J = 1.5, 7.4 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 46.18, 52.96, 54.69, 55.78,
70.48, 114.54, 114.97, 143.45, 152.76, 157.59.
tert-Butyl 2-Hydroxypropyl(phenyl)carbamate (4g)
Following the general procedure using 1g (151 mg, 1.00 mmol) and
Boc2O (218 mg, 1.00 mmol); column chromatography (silica gel,
hexanes–EtOAc, 7:3) gave 4g (224 mg, 89%) as a colorless oil.
IR (NaCl): 3398, 3083, 1774, 1606, 1086, 986 cm–1.
Anal. Calcd for C12H16ClNO4: C, 52.66; H, 5.89; N, 5.12.Found: C,
52.80; H, 5.98; N, 5.28.
1H NMR (250 MHz, CDCl3): d = 1.13 (d, J = 6.3 Hz, 3 H), 1.40 (s,
9 H), 3.50 (dd, J = 3.6, 14.1 Hz, 2 H), 3.66 (br s, 1 H), 3.91 (m, 1
H), 7.12–7.34 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 20.99, 28.24, 57.99, 66.88,
80.83, 126.34, 127.14, 128.84, 142.92, 156.20.
Methyl 3-Chloro-2-hydroxypropyl(3-fluoro-4-morpholinophe-
nyl)carbamate (5e)
Following the general procedure using 1e (289 mg, 1.00 mmol) and
methyl chloroformate (945 mg, 10.00 mmol); column chromatogra-
phy (silica gel, hexanes–EtOAc, 7:3) gave 5e (347 mg, quant.) as a
brown oil.
Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C,
67.03; H, 8.28; N, 5.45.
IR (NaCl): 3315, 1769, 1648, 1530, 1463, 1116 cm–1.
N-Moc and N-Cbz Protection of Amino Alcohols; General Pro-
cedure
1H NMR (250 MHz, CDCl3): d = 3.03 (td, J = 4.5, 9.0 Hz, 4 H), 3.51
(dd, J = 5.0, 11.1 Hz, 1 H), 3.69 (dd, J = 3.9, 14.4 Hz, 2 H), 3.70 (br
s), 3.74 (s, 3 H), 3.85 (dd, J = 4.5, 9.0 Hz, 4 H), 4.03 (m, 1 H), 6.83–
7.06 (m, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 47.18, 50.70, 51.16, 66.90,
70.15, 115.51 (d, 2JC,F = 18.8 Hz), 118.50 (d, 4JC,F = 3.1 Hz), 123.14
(d, 4JC,F = 2.5 Hz), 136.12 (d, 3JC,F = 7.5 Hz), 138.96 (d, 3JC,F = 7.5
Hz), 155.29 (d, 1JC,F = 244.4 Hz), 156.63.
The amino alcohol (1.00 mmol) was dissolved in MeOH–H2O (5
mL, 1:1) and cooled to 0 °C. Alkyl chloroformate (10 mmol) was
then added dropwise and immediately followed by K2CO3 (10
mmol). When the reaction was complete (TLC), the mixture was
extracted with CH2Cl2 (3 × 15 mL), dried (Na2SO4), and evaporated
in vacuo. The residue was purified by column chromatography (sil-
ica gel).
19F NMR (235 MHz, CDCl3): d = –165.72 (br s).
Methyl 3-Chloro-2-hydroxypropyl(phenyl)carbamate (5a)
Following the general procedure using 1a (186 mg, 1.00 mmol) and
methyl chloroformate (945 mg, 10.00 mmol); column chromatogra-
phy (silica gel, hexanes–EtOAc, 4:1) gave 5a (231 mg, 95%) as a
colorless oil.
Anal. Calcd for C15H20ClFN2O4: C, 51.95; H, 5.81; N, 8.08. Found:
C, 52.06; H, 5.70; N, 7.96.
Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted a-Arylamino-a¢-chloropropan-2-ones
3553
Methyl 3-Chloro-2-hydroxypropyl(3,4-difluorophenyl)car-
bamate (5f)
Following the general procedure using 1f (222 mg, 1.00 mmol) and
methyl chloroformate (945 mg, 10.00 mmol); column chromatogra-
phy (silica gel, hexanes–EtOAc, 4:1) gave 5f (263 mg, 94%) as a
brown oil.
Methyl 3-Chloro-2-oxopropyl(4-methoxyphenyl)carbamate
(10)
Following the general procedure for Dess–Martin oxidation using
5c (136 mg, 0.50 mmol) and DMP (254 mg, 0.60 mmol) gave 10
(122 mg, 90%) as a colorless solid; mp 67 °C.
IR (NaCl): 3086, 1765, 1740, 1468, 1229, 1180 cm–1.
IR (NaCl): 3432, 1766, 1623 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.72 (s, 3 H), 3.81 (s, 3 H), 4.22
(s, 2 H), 4.63 (s, 2 H), 6.67 (dd, J = 1.7, 7.8 Hz, 2 H), 6.90 (dd,
J = 1.7, 7.8 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 46.98, 52.17, 52.38, 57.54,
115.67, 118.60, 134.33, 155.67, 157.45, 199.14.
1H NMR (250 MHz, CDCl3): d = 3.25 (dd, J = 7.5, 13.6 Hz, 1 H),
3.46 (dd, J = 3.8, 13.6 Hz, 2 H), 3.68 (s, 3 H), 3.71–3.79 (m, 2 H),
4.12 (m, 1 H), 6.43 (m, 1 H), 6.57 (m, 1 H), 7.38 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 48.21, 49.30, 50.90, 70.68,
2
4
4
103.97 (d, JC,F = 23.6 Hz), 109.89 (dd, JC,F = 2.9 Hz, JC,F = 5.3
Anal. Calcd for C12H14ClNO4: C, 53.05; H, 5.19; N, 5.16. Found: C,
53.20; H, 5.03; N, 5.31.
4
2
Hz), 119.07 (dd, JC,F = 2.2 Hz, JC,F = 18.8 Hz), 144.25 (dd,
3JC,F = 15.0 Hz, JC,F = 239.8 Hz), 148.15 (dd, JC,F = 2.2 Hz,
1
4
3JC,F = 9.0 Hz), 153.73 (dd, JC,F = 15.0 Hz, JC,F = 246.6 Hz),
3
1
tert-Butyl 3-Chloro-2-oxopropyl(4-nitrophenyl)carbamate (11)
Following the general procedure for Dess–Martin oxidation using
4d (198 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol) gave 11
(193 mg, 98%) as a yellow solid; mp 86 °C.
156.18.
19F NMR (235 MHz, CDCl3): d = –163.54 (br s).
Anal. Calcd for C11H12ClF2NO3: C, 47.24; H, 4.32; N, 5.01. Found:
C, 47.19; H, 4.46; N, 5.19.
IR (NaCl): 2987, 1769, 1743, 1539, 1514, 1456, 1313, 1193, 1098,
1001 cm–1.
tert-Butyl 3-Chloro-2-oxopropyl(phenyl)carbamate (7)
Following the general procedure for Dess–Martin oxidation using
4a (171 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol) gave ke-
tone 7 (170 mg, quant.) as a colorless solid; mp 84 °C.
IR (NaCl): 3086, 1765, 1741, 1636 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.45 (s, 9 H), 4.19 (s, 2 H), 4.58
(s, 2 H), 7.21–7.38 (m, 5 H).
1H NMR (250 MHz, CDCl3): d = 1.49 (s, 9 H), 4.21 (s, 2 H), 4.64
(s, 2 H), 6.65 (dd, J = 2.3, 9.6 Hz, 2 H), 8.09 (dd, J = 2.3, 9.6 Hz, 2
H).
13C NMR (62.5 MHz, CDCl3): d = 28.01, 45.60, 56.75, 85.47,
112.34, 127.29, 138.98, 148.14, 153.89, 198.25.
Anal. Calcd for C14H17ClN2O5: C, 51.15; H, 5.21; N, 8.52. Found:
C, 51.34; H, 5.09; N, 8.67.
13C NMR (62.5 MHz, CDCl3): d = 27.12, 45.30, 56.60, 80.41,
125.46, 125.94, 127.85, 141.43, 156.12, 197.30.
Methyl 3-Chloro-2-oxopropyl(3-fluoro-4-morpholinophe-
nyl)carbamate (12)
Following the general procedure for Dess–Martin oxidation using
5e (208 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol) gave 12
(193 mg, 97%) as a reddish solid; mp 71 °C.
Anal. Calcd for C14H18ClNO3: C, 59.16; H, 6.39; N, 4.94. Found: C,
59.30; H, 6.16; N, 5.08.
Methyl 3-Chloro-2-oxopropyl(phenyl)carbamate (8)
Following the general procedure for Dess–Martin oxidation using
5a (146 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol); column
chromatography (silica gel, hexanes–EtOAc, 4:1) gave 8 (138 mg,
95%) as a colorless solid; mp 76 °C.
IR (NaCl): 3086, 1756, 1737 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.71 (s, 3 H), 4.17 (s, 2 H), 4.64
(s, 2 H), 7.28 (d, J = 7.5 Hz, 3 H), m, (m, 2 H).
IR (NaCl): 3083, 1771, 1735, 1665, 1526, 1457, 1121 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.07 (dd, J = 4.7, 9.5 Hz, 4 H),
3.71 (s, 3 H), 3.84 (dd, J = 4.7, 9.5 Hz, 4 H), 4.16 (s, 2 H), 4.60 (s,
2 H), 6.89 (m, 1 H), 7.02 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 46.26, 53.50, 55.73, 57.80,
66.92, 114.79, 118.47, 122.92, 137.15, 139.63, 155.10, 157.36,
197.96.
13C NMR (62.5 MHz, CDCl3): d = 46.33, 53.44, 57.82, 127.87,
19F NMR (235 MHz, CDCl3): d = –165.86 (br s).
127.22, 129.17, 141.83, 157.16, 198.01.
Anal. Calcd for C15H18ClFN2O4: C, 52.26; H, 5.26; N, 8.13. Found:
C, 52.42; H, 5.14; N, 7.92.
Anal. Calcd for C11H12ClNO3: C, 54.67; H, 5.00; N, 5.80. Found: C,
54.78; H, 5.13; N, 5.93.
Methyl 3-Chloro-2-oxopropyl(3,4-difluorophenyl)carbamate
(13)
Following the general procedure for Dess–Martin oxidation using
5f (168 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol) gave 13
(165 mg, 99%) as a white solid; mp 49 °C.
Benzyl 3-Chloro-2-oxopropyl(phenyl)carbamate (9)
Following the general procedure for Dess–Martin oxidation using
6a (192 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol) gave 9
(175 mg, 92%) as a colorless solid; mp 91 °C.
IR (NaCl): 3082, 1761, 1735 cm–1.
IR (NaCl): 1771, 1746, 1627, 989 cm–1.
1H NMR (250 MHz, CDCl3): d = 4.21 (s, 2 H), 4.61 (s, 2 H), 5.21
(s, 2 H), 6.76–6.84 (m, 3 H), 7.24–7.35 (m, 5 H), 7.39–7.46 (m,
5 H).
13C NMR (62.5 MHz, CDCl3): d = 45.11, 53.14, 69.18, 113.63,
118.00, 128.34, 128.45, 128.75, 130.43, 135.29, 148.18, 157.65,
198.15.
1H NMR (250 MHz, CDCl3): d = 3.73 (s, 3 H), 4.19 (s, 2 H), 4.58
(s, 2 H), 7.23–7.36 (m, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 46.73, 53.12, 56.01, 111.53,
113.24, 119.04, 125.52, 139.12, 145.65, 157.92, 196.13.
19F NMR (235 MHz, CDCl3): d = –162.59 (br s).
Anal. Calcd for C11H10ClF2NO3: C, 47.58; H, 3.63; N, 5.04. Found:
C, 47.39; H, 3.70; N, 5.18.
Anal. Calcd for C17H16ClNO3: C, 64.26; H, 5.08; N, 4.41. Found: C,
64.37; H, 5.24; N, 4.25.
Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York

3554
V. Pace et al.
PAPER
tert-Butyl 2-Oxopropyl(phenyl)carbamate (14)
13C NMR (62.5 MHz, CDCl3): d = 46.61, 53.09, 107.43, 116.39,
Following the general procedure for Dess–Martin oxidation using
4g (151 mg, 0.60 mmol) and DMP (305 mg, 0.72 mmol) gave 12
(141 mg, 94%) as a reddish solid; mp 56 °C.
IR (NaCl): 3083, 1771, 1735, 1665, 1526, 1457, 1121 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.44 (s, 3 H), 2.19 (s, 3 H), 4.22
(s, 2 H), 7.18–7.35 (m, 5 H).
121.98, 136.14, 139.65, 144.37, 201.67.
19F NMR (235 MHz, CDCl3): d = –162.20 (br s).
Anal. Calcd for C9H8ClF2NO: C, 49.22; H, 3.67; N, 6.38. Found: C,
49.44; H, 3.78; N, 6.53.
Computational Methods Validation
All the electronic structure calculations were performed by mean of
the Massively Parallel Quantum Chemistry (MPQC) package.31 All
structures were optimized by density functional theory (DFT) meth-
ods at 6-311++G(2d,2p) level with B3LYP functional. The optimi-
zations were performed for the molecule with intramolecular
hydrogen bonds and for the corresponding conformers without such
interactions. Counterpoise correction was used to take into account
the basis set superposition error. To obtain energies for intermolec-
ular hydrogen bonds, molecular dynamics performed with GRO-
MACS package (version 4.0.4)32 were used. Solvent and reactants
were parameterized using the OPLS/AA force field33 with ACPYPI
and Amber10 tools (Antechamber).34 CH2Cl2 was parameterized
combining parameters from the force field and geometry and charge
from AM1 semiempirical calculations. To validate the model, den-
sity and enthalpy of vaporization were used. All MD simulations
were performed with an identical protocol: 4000 steps of steepest
descents (SD) followed by a 3000 steps of Polak–Ribiere conjugate
gradient (CG) to minimize the energy of the system. After minimi-
zation, 300 ps of NVT equilibration followed by 100 ps of NPT
equilibration were carried out. Finally a production simulation of 5
ns was performed. Particle–Mesh–Ewald summation35 was applied
dealing with long-range electrostatics and a 1.4 nm cut-off for Van
der Waals interactions was used. MD simulations of the compounds
solvated in a CH2Cl2 box were analyzed to obtain the thermodynam-
ic properties of hydrogen bonds between molecules using the
g_hbond tool36 included in GROMACS.
13C NMR (62.5 MHz, CDCl3): d = 22.19, 28.35, 57.99, 80.89,
126.97, 128.64, 129.69, 141.59, 157.04, 198.19.
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.59; H, 6.43; N, 6.84.
TMSI-Promoted Carbamate Cleavage; General Procedure
To a cooled soln (–20 °C) of carbamate 7–14 (0.30 mmol) in
CH2Cl2 (10 mL), TMSI (0.30 mmol, 1.00 equiv) was added drop-
wise over 15 min. The mixture was stirred at –20 °C for 1 h and then
at 0 °C until complete consumption of substrate (TLC, 3–24 h). H2O
(5 mL) was added and the organics were extracted with CH2Cl2
(2 × 15 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
Pure unprotected ketones 15–20 were recovered after purification
by column chromatography (silica gel).
1-Chloro-3-(4-methoxyphenylamino)propan-2-one (16)
Following the general procedure for carbamate cleavage using 10
(81 mg, 0.30 mmol) and TMSI (60 mg, 0.30 mmol) for 24 h; chro-
matography (petroleum ether–EtOAc, 7:3) gave 16 (46 mg, 71%) as
a colorless solid; mp 84 °C.
IR (NaCl): 3395, 3081, 1726, 1597, 1493, 1238, 1189 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.79 (s, 3 H), 4.04 (br s), 4.12 (s,
2 H), 4.55 (s, 2 H), 6.74 (dd, J = 1.3, 8.2 Hz, 2 H), 6.83 (dd, J = 1.3,
8.2 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 46.15, 54.23, 56.16, 115.14,
117.54, 141.16, 153.46, 200.32.
Regarding molecular liquids, the comparison between experimental
and theoretical values for liquid density and enthalpy of vaporiza-
tion is a relevant criterion to validate the force field parameteriza-
tion. The enthalpy of vaporization was calculated assuming the
following approximation:
Anal. Calcd for C10H12ClNO2: C, 56.21; H, 5.66; N, 6.56. Found: C,
56.39; H, 5.54; N, 6.68.
1-Chloro-3-(3-fluoro-4-morpholinophenylamino)propan-2-one
(18)
DHn ≈ –Ecohesion + RT
Following the general procedure for carbamate cleavage using 12
(103 mg, 0.30 mmol) and TMSI (60 mg, 0.30 mmol) for 24 h; chro-
matography (hexanes–EtOAc, 3:2) gave 18 (65 mg, 75%) as a
brown solid; mp 95 °C.
where Ecohesion is the total cohesion energy per particle (216 in the
case of the simulation), R is the gas constant and T the temperature.
The average values obtained from the 5 ns simulation, 1.2981 g/mL
for density and 26.49 kJ/mol for enthalpy of vaporization are in
good agreement with experimental data available (d = 1.3180 g/mL,
DHn = 28.381 kJ/mol)37 and therefore, the parameters can be ac-
cepted.
IR (NaCl): 3403, 3083, 1739, 1659, 1536, 1491, 1111 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.04 (dd, J = 5.0, 9.8 Hz, 4 H),
3.75 (dd, J = 5.0, 9.8 Hz, 4 H), 4.07 (br s), 4.14 (s, 2 H), 4.39 (s, 2
H), 6.71 (m, 1 H), 6.89 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 46.10, 53.21, 54.96, 66.12,
116.37, 119.56, 123.64, 139.23, 141.45, 152.16, 303.13.
Acknowledgment
One of the Authors (V. Pace) thanks the Spanish Ministry of Sci-
ence and Innovation for a Predoctoral Grant (Ref. FPU-2005-5112).
19F NMR (235 MHz, CDCl3): d = –165.51 (br s).
Anal. Calcd for C13H16ClFN2O2: C, 54.46; H, 5.62; N, 9.77. Found:
C, 54.59; H, 5.74; N, 9.93.
References
1-Chloro-3-(3,4-difluorophenylamino)propan-2-one (19)
Following the general procedure for carbamate cleavage using 13
(83 mg, 0.30 mmol) and TMSI (60 mg, 0.30 mmol) for 16 h; chro-
matography (hexanes–EtOAc, 9:1) gave 19 (53 mg, 81%) as a col-
orless solid; mp 66 °C.
IR (NaCl): 3423, 1725, 1597, 1493 cm–1.
1H NMR (250 MHz, CDCl3): d = 4.09 (br s), 4.14 (s, 2 H), 4.45 (s,
2 H), 6.75 (m, 1 H), 7.01 (m, 1 H), 7.33 (m, 1 H).
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Synthesis 2010, No. 20, 3545–3555 © Thieme Stuttgart · New York