Amidation of esters with amino alcohols using organobase catalysis

Article abstract of DOI:10.1021/jo501929c

A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate.

Full text of DOI:10.1021/jo501929c

Article
pubs.acs.org/joc
Amidation of Esters with Amino Alcohols Using Organobase
Catalysis
Nicola Caldwell,∥ Peter S. Campbell,∥ Craig Jamieson,*,∥ Frances Potjewyd,∥ Iain Simpson,‡
and Allan J. B. Watson∥
∥Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
‡Oncology Innovative Medicines, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
S
* Supporting Information
ABSTRACT: A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is
reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification,
followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the
synthesis of oxazolidinone systems through use of dimethyl carbonate.
The reaction was posited to proceed through an initial
transesterification event mediated by BEMP which liberates 1
equiv of alkoxide base capable of catalyzing a further reaction
cycle. Rearrangement of the intermediate ester is then thought
to lead to the thermodynamically more stable amide product 1.
In this study, we present our work in relation to the mechanistic
aspects of this base-catalyzed process, as well as a complete
report on the scope and limitations of the reaction. Additionally,
we demonstrate the applicability of the process to a new reaction
manifold enabling the synthesis of oxazolidinone derivatives.
INTRODUCTION
■
The amide bond is a pivotal functional group from consideration
of both chemistry and biology.1,2 In an industrial context,
formation of the amide bond represents the single largest subset
of all reactions conducted in medicinal chemistry laboratories,3,4
which further underlines the importance of this ubiquitous
functionality. Accordingly, considerable investment has been
made in the development of synthetic methodology which
enables this transformation in a mild and efficient manner, and a
broad palette of reagents has now emerged from these efforts.5
However, the majority of reagents currently available to facilitate
amide bond formation are stoichiometric in nature, and the poor
atom economy associated with their use has prompted calls for
their replacement by more efficient and sustainable alternatives.6
Given the urgent requirement to address this important issue, a
number of catalytic approaches to amide bond formation have
emerged in recent years.7 For example, these methods include
the use of transition metal catalysts,8−10 boron-derived
species,11−13 or enzymes.14 Although many of these catalytic
processes have wide utility, they are often associated with some
limitations, including use of high temperatures, unsustainable
rare earth metals, or extended reaction times.
We recently reported a base-mediated process for the catalytic
preparation of amides from esters and amino alcohol
derivatives.15 Through a combination of reaction screening
where we explored a range of organic and inorganic bases and
application of Design of Experiments optimization methods,16 it
was possible to develop a mild, efficient, and unprotracted
procedure for the synthesis of amides from unactivated ester
derivatives and amino alcohols using a catalytic (10 mol %)
quantity of tert-butylimino-2-diethylamino-1,3-dimethylperhy-
dro-1,3,2-diazaphosphorine (BEMP, 2)17 as a base (Scheme 1).
RESULTS AND DISCUSSION
■
Investigation into Reaction Mechanism. As intimated in
Scheme 1, we reasoned that the reaction proceeds via an initial
transesterification process, to yield an intermediate ester
represented by 4. On the basis of this, we aimed to
independently prepare a compound of this type and determine
if it was capable of undergoing the requisite rearrangement to
the observed amide product. Scheme 2 depicts the preparation
of an appropriate test substrate, using a 1,1′-carbonyldiimidazole
(CDI)-mediated esterification,18 followed by acidolysis of the
Boc protecting group to yield the salt 6. We initially attempted
to isolate intermediate ester 6 using the conditions established
in Scheme 1 (10 mol % BEMP in MeCN); however, this was not
successful, as presumably the esterification is reversible if
rearrangement to the amide cannot take place. Treatment of 6
with an organic base then enabled smooth conversion to the
desired amide product 7 in high yield (95%). This result
Received: August 20, 2014
© XXXX American Chemical Society
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Scheme 1. Organobase-Mediated Amidation of Esters with Amino Alcohols
Scheme 2. Preparation of an Ester Intermediate To Probe Mechanism
Scheme 3. Competition Experiment
Figure 1. Mechanistic probes evaluated. (a) Reaction performed at 40 °C.
indicated that the intermediate esters represented by 4 (Scheme
1) were competent in rearranging to the amide product.
Previously, we had considered this process to be intra-
molecular in nature. Accordingly, we designed a series of probe
molecules to confirm this proposal and exclude any potential
intermolecular amidation pathways. In the first instance, we
conducted a competition experiment, condensing ethanolamine
and propylamine with methyl phenylacetate (Scheme 3). In this
case, the exclusive product obtained was ethanolamine-derived
amide 8 in high yield, supporting the view that a more favorable
transesterification and subsequent intramolecular rearrange-
ment was operative.
With this information in hand, we then designed a series of
probe molecules which could offer additional support to the
notion of an intramolecular rearrangement. Accordingly, we
examined the effect of homologation of the amino alcohol
partner on reaction yield (Figure 1). Increasing the chain length
would be anticipated to have a deleterious effect on conversion
due to the increased flexibility of the system, which then
disfavors the required rearrangement of the proposed
intermediate ester to the target amide. Additionally, when
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increasing the chain length of the amino alcohols, the cyclic
transition states arising from the proposed intramolecular
rearrangement increase from a five-membered ring with
ethanolamine, through to an eight-membered ring with
pentanolamine. The strain associated with the differing cycle
sizes are calculated as follows: five-membered, 6 kcal/mol; six-
membered, 0.1 kcal/mol; seven-membered, 6.2 kcal/mol; eight-
membered, 9.7 kcal/mol.19 From consideration of this aspect of
the reaction, it can again be reasoned that longer chain amino
alcohols should be less competent substrates. If an intermo-
lecular process leading to a direct amidation was applicable, then
it could be anticipated that the reaction yield would not be
significantly affected by homologation over the range examined
in the current study. Consideration of a range of products with
increasing chain length (8, 10a−c, Figure 1) under the standard
conditions outlined in Scheme 1 confirms this to be the case;
extending the chain length to the butanolamine analogue 10b
results in a significant erosion in yield compared to 10a, with the
pentanolamine system 10c completely failing to form. The effect
of the acidic pKa of the alcohol moiety is not believed to
influence the observed yield; if an increase in acidic pKa was
noted then it would disfavor initial deprotonation and retard the
overall process. Consideration of the relevant pKa values for
propanolamine, butanolamine, and pentanolamine are all
around 15,20 indicating that the differences in reactivity
observed in homologating the amino alcohol species are
unlikely to be attributable to changes in pKa. These results
lend further credence to the initial hypothesis of an intra-
molecular rearrangement following transesterification.
We next examined a further set of substrates (10d−f, Figure
1) which could provide additional evidence in support of our
proposed mechanism. The 4-hydroxypiperidine amide 10d is a
conformationally locked analogue of the propanolamine
derivative 10a and was thus anticipated to be too constrained
to undergo rearrangement to the amide following trans-
esterification, which is consistent with the conversion observed
in this case. Additionally, the benzylamine-derived product 10e
is not an effective substrate from both enthalpic and entropic
considerations. An analogous amide product 10f was success-
fully isolated, albeit in reduced yield in comparison to aliphatic-
based progenitors, indicating the tolerance of phenols as
substrates. By contrast, however, the isomeric amide system
10g did not form under the standard conditions developed,
presumably due to the lower nucleophilicity of the aniline in the
context of the ester rearrangement, which indicates a potential
limitation of the current approach with this class of substrate.
In the last part of this aspect of the study, we sought to
establish relative rates of conversion between a secondary amine
in comparison with a primary amine and upon comparing an
amino diol with an amino alcohol. Compounds 11a and 11b
(Figure 2) could be isolated in excellent yields (91% and 88%,
respectively) using the existing protocol, and these were used
together with compound 8 to assess conversion to each product
as a function of time. The data which emerged from this
experiment indicated rapid conversion to product in each case
and in a relatively short time frame (less than 1 h). There was
little difference between any of the substrates in terms of their
rates of conversion, with the amino diol 11b exhibiting a
marginally faster temporal profile. No evidence for the
corresponding ester intermediates could be detected in the
HPLC assay, suggesting this is potentially the rate-determining
step and that rearrangement to amide product is extremely rapid
in each case.
Figure 2. Assessment of conversion as a function of time. (a)
Determined by HPLC using an internal standard.
Scope of the Amidation Process. In the second part of
this study, we aimed to more fully delineate the scope of the
reaction. To evaluate this, a broad range of ester derivatives and
amino alcohols were examined using the established reaction
conditions (10 mol % BEMP, MeCN, room temperature or 40
°C, 15 h), and the results of this survey are presented in Figure
3. Various substituted benzamide systems (12a−e) can be
readily accessed and in good to excellent yield. Again, where
yields are lower at room temperature, application of modest
heating (12b) is effective in furnishing high yields. Aliphatic
ester derivatives (12f−h) also perform well in the reaction
which is useful for the synthesis of lead-like compounds21 in a
discovery chemistry setting exemplified by 12g and 12h. In
relation to this, the synthesis of heterocyclic amide derivatives is
an important objective in a medicinal chemistry effort;22
therefore, evaluation of the current methodology using such
substrates is warranted. Accordingly, a raft of different
heterocyclic motifs exemplified by compounds 12i−t were
examined. Pyridine (12i, 12l), pyrimidine (12k, 12p), pyrazine
(12j), pyrrole (12o), thiophene (12q), and furan (12r) all
perform well along with saturated heterocyclic motifs such as
12s and lead-like architectures such as 12t. Focusing on the
triazole-derived motifs, compound 12m was isolated in a low
yield of 28%. However, we attribute this to the poor solubility of
both the ester starting material and product itself in the reaction
solvent. By contrast, the corresponding methylated analogue
12n is completely soluble in the reaction milieu, which is
reflected in the excellent yield (94%) obtained with this
compound.
Additionally, to enable a direct comparison between the
current catalytic approach and existing stoichiometric methods,
we independently prepared the pyrimidine derivative 12p using
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexa-
fluorophosphate (HATU)23 as a coupling agent with the
corresponding carboxylic acid (Scheme 4). Pleasingly, the
catalytic approach described here performs well in comparison
to a standard coupling reagent, furnishing 12p in a slightly
improved yield over the existing method, with the clear
advantage of obviating the need for stoichiometric reagents
and generation of associated byproducts.
In addition to the straight-chain amino alcohol systems
discussed above, we also examined further range of substrates as
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Figure 3. Scope of amide synthesis with straight chain amino alcohols. (a) Reaction performed at 40 °C.
excellent yield, which serves to demonstrate the utility of the
method for larger scale synthesis. Other amino alcohols derived
from proteinogenic amino acids such as phenylalaninol were
also competent substrates in the reaction (13f), allowing access
to peptidic structures. Further evaluation of secondary amine
derivatives as nucleophiles showed these to be robust substrates
as exemplified by compounds 13g and 13h. As discussed above,
amino diols performed well in the reaction, and amide 13i is a
further example of this substrate class. Secondary and tertiary
alcohols represent a more significant challenge which can be
ascribed to a more demanding initial transesterification reaction.
However, application of modest heating enabled the isolation of
13j in good yield using our catalytic process. In the case of
Scheme 4. Comparative Synthesis of 12b with Stoichiometric
Reagents
outlined in Figure 4. (S)-Prolinol proved to be an effective
nucleophile with benzoate esters (13a), cinnamate derivatives
(13b), and heterocyclic systems (13c, 13d) as well as alkyl
esters (13e). Amide 13a was also prepared from methyl 4-
bromo-2-chlorobenzoate and (S)-prolinol on a 2.5 g scale in
Figure 4. Scope of amino alcohol component: (a) 2.5 g scale input; (b) performed at 40 °C.
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tertiary alcohols, we could not prepare amides from electron-
neutral substrates such as methyl phenylacetate (leading to
13k), suggesting a possible limitation of the methodology.
However, when more electron-withdrawing esters are em-
ployed, the corresponding products such as 13l can be isolated
in preparatively useful yield. It was not possible to identify any
ester intermediate in the reaction to form 13l, indicating rapid
rearrangement to the thermodynamically favorable amide, as
noted previously.
In the concluding part of our study, we turned our attention
to application of the methodology to the synthesis of
oxazolidinone derivatives. These important heterocyclic motifs
are used widely in both asymmetric synthesis24 and medicinal
chemistry;25 therefore, a mild and efficient approach to their
synthesis would be attractive. Typically, oxazolidinones are
synthesized by the reaction of a suitable amino alcohol and
diethyl carbonate in the presence of excess base (e.g., K2CO3,
NaOMe) while heating, usually to temperatures in excess of 100
°C.26 Given that we had established that formation of an
intermediate ester followed by cyclization to an amide was
taking place in the amidation reaction, it was reasoned that this
could be exploited in the synthesis of oxazolidinones. Adapting
the reaction conditions outlined above could potentially offer a
favorable alternative to the typical synthesis of such compounds,
having the advantage of being performed at significantly lower
temperatures and through the use of catalytic amounts of base.
A brief survey of stoichiometry of the dimethyl carbonate
(DMC) starting material was carried out in a model reaction
with phenylalaninol (Table 1). Given the low cost and
ment to explore the synthesis of a small range of oxazolidinone
derivatives using this approach (Figure 5).
Considering the focused subset outlined in Figure 5, a range
of oxazolidinone derivatives could be prepared using an
appropriate amino alcohol and dimethyl carbonate under
relatively mild conditions using catalytic BEMP and in generally
good yield. Amino alcohols derived from proteinogenic amino
acids were very effective in the reaction (14a−c, 14e), while
ethanolamine gave acceptable yields of oxazolidin-2-one (14d).
Amino diols were also tolerated in this process, leading to
products such as 14f in excellent isolated yield.
CONCLUSION
■
A mild and efficient synthesis of amide derivatives from esters
and amino alcohols has been reported using an organic base as a
catalyst. The full scope of the reaction has been evaluated
including application toward amide products of potential
pharmaceutical relevance and extension of the methodology
toward the preparation of the versatile oxazolidinone motif.
Additionally, through design and study of appropriate probe
molecules, the mechanism of the reaction has been delineated,
indicating that an initial transesterification is taking place,
followed by rapid and facile rearrangement to the corresponding
amide products.
EXPERIMENTAL SECTION
■
General Methods. All reagents and solvents were used as obtained
unless otherwise stated. Purification was carried out according to
standard laboratory methods.27 BEMP was purified by vacuum
distillation from CaH2 and stored in a septum-sealed oven-dried flask
over previously activated 4 Å molecular sieves and purged with and
stored under nitrogen. Reactions were carried out under Schlenk
conditions using oven-dried glassware, which was evacuated and purged
with N2 before use. Thin layer chromatography was carried out using
aluminum-backed silica plates which were analyzed under 254 nm UV
light or developed using potassium permanganate solution. Flash
Table 1. Survey of Conditions for Oxazolidinone Synthesis
1
chromatography was carried out using prepacked silica cartridges. H
NMR spectra were recorded at 400 or 500 MHz, and 13C NMR spectra
were recorded at 101 or 126 MHz. Chemical shifts are reported in ppm,
and coupling constants are reported in hertz with CDCl3 referenced at
7.27 (1H) and 77.23 ppm (13C), and DMSO referenced at 2.50 (1H)
and 39.51 ppm (13C). Mass spectrometry data was generated using a
TOF analyzer. Optical rotations were measured at 589 nm, with
concentrations reported in grams per 100 mL. Conversions were
determined by HPLC using iodobenzene as an internal standard. The
data for products 8, 12a, 12b, 12c, 12f, 12i, 12q, 12r, 13c, 13e, 13f, and
13j were reported in our earlier communication.15
a
entry
dimethyl carbonate (equiv)
conversion (%)
1
2
3
4
1
68
72
69
61
3
5
6 (neat)
a
Determined by HPLC using an internal standard.
2-((tert-Butoxycarbonyl)amino)ethyl Benzoate (5).28 To a solution
of benzoic acid (341 mg, 2.8 mmol) in CH2Cl2 (2 mL) were added CDI
(456 mg, 3 mmol) and Et3N (418 μL, 3 mmol). The reaction mixture
was stirred at room temperature for 16 h, washed with water, dried
(MgSO4), filtered, and then concentrated to a residue that was purified
by flash column chromatography (25% ethyl acetate/petroleum ether)
to afford the title compound as a white solid (653 mg, 88%): νmax
(neat) 3375, 1701, 1530 cm−1; 1H NMR (500 MHz, CDCl3): δH 8.07−
8.04 (m, 2H), 7.58 (tt, J = 7.5, 1.5 Hz, 1H), 7.47−7.43 (m, 2H), 4.87
abundance of DMC in relation to the amino alcohol precursors,
we elected to use an excess of this reagent. To afford the highest
probability of success, we also examined the use of slightly
elevated temperatures from the outset.
Pleasingly, we observed good levels of conversion to the
desired product in each of the reactions attempted. From this
short screening exercise, we confirmed that 3 equiv of the
carbonate component was optimal, which provided encourage-
Figure 5. Application to the synthesis of oxazolidinone systems.
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(br s, 1H), 4.39 (t, J = 5.5 Hz, 2H); 3.54 (d, J = 4.5 Hz, 2H), 1.45 (s,
9H); 13C NMR (126 MHz, CDCl3) δC 166.7, 156.0, 133.3, 130.1,
130.0, 128.6, 79.8, 64.5, 40.0, 28.6; HRMS (ESI) m/z: [M + Na]+ calcd
for C14H19NO4Na 288.1204, found 288.1204.
40.6, 33.9; HRMS (ESI) m/z: [M + H]+ calcd for C11H16NO2
194.1176, found 194.1173.
N,N-Bis(2-hydroxyethyl)-2-phenylacetamide (11b). White solid
1
(279 mg, 88%): νmax (neat) 3329, 3204, 2903, 1601, 1479 cm−1; H
NMR (500 MHz, DMSO): δH 7.31−7.28 (m, 2H), 7.22−7.20 (m, 3H),
4.86 (t, J = 5.3 Hz, 1H), 4.65 (t, J = 5.3 Hz, 1H), 3.73 (s, 2H), 3.52 (q, J
= 5.7 Hz, 2H), 3.48 (q, J = 5.9 Hz, 2H), 3.43 (t, J = 5.8 Hz, 2H), 3.36 (t,
J = 6.2 Hz, 2H); 13C NMR (126 MHz, DMSO) δC 170.6, 136.3, 129.0,
128.2, 126.2, 59.2, 58.8, 50.8, 48.4, 1C missing (coincident); HRMS
(ESI) m/z: [M + Na]+ calcd for C12H17NO3Na 246.1101, found
246.1099.
2-(Benzoyloxy)ethanaminium 2,2,2-Trifluoroacetate (6). To a
solution of 2-((tert-butoxycarbonyl)amino)ethyl benzoate (5, 398
mg, 1.5 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1
mL). The reaction mixture was stirred at room temperature for 16 h,
heated at 40 °C for 24 h, and then concentrated under vacuum to afford
the title compound as a white solid (381 mg, 91%): νmax (neat) 3330,
1
3107, 2967, 1725, 1544 cm−1; H NMR (500 MHz, DMSO) δH 8.09
3-Bromo-N-(2-hydroxyethyl)benzamide (12d). White solid (343
(dd, J = 8.2, 1.3 Hz, 2H), 8.03 (br s, 2H), 7.69 (tt, J = 7.3, 1.3 Hz, 1H),
7.57−7.54 (m, 2H), 4.44 (t, J = 5.8 Hz, 2H), 3.25 (q, J = 4.7 Hz, 2H),
1H missing (exchangeable); 13C NMR (126 MHz, DMSO) δC 165.6,
133.6, 129.6, 129.3, 128.6, 61.5, 38.0; HRMS (ESI) m/z: [M]+ calcd for
C9H12NO2 166.0863, found 166.0858.
1
mg, 99%): νmax (neat) 3360, 3291, 3065, 2951, 1636, 1541 cm−1; H
NMR (500 MHz, DMSO) δH 8.55 (t, J = 5.2 Hz, 1H), 8.04 (t, J = 1.8
Hz, 1H), 7.86−7.84 (m, 1H), 7.72 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.43
(t, J = 7.9 Hz, 1H), 3.51 (t, J = 6.2 Hz, 2H), 3.32 (q, J = 6.1 Hz, 2H), 1H
missing (exchangeable); 13C NMR (126 MHz, DMSO) δC 164.8,
136.7, 133.8, 130.5, 129.9, 126.3, 121.6, 59.6, 42.3; HRMS (ESI) m/z:
[M + Na]+ calcd for C9H10BrNO2Na 265.9784, found 265.9785.
2-Bromo-N-(2-hydroxyethyl)benzamide (12e). White solid (332
N-(2-Hydroxyethyl)benzamide (7).15 To a solution of 2-aminoethyl
benzoate (6, 381 mg, 1.37 mmol) in CH2Cl2 (3 mL) was added Et3N
(226 μL, 1.64 mmol). The reaction mixture was stirred at room
temperature for 16 h and then concentrated to a residue that was
purified by flash column chromatography (5% methanol/CH2Cl2) to
afford the title compound as a white solid (306 mg, 95%): νmax (neat)
3296, 2937, 2876, 1634, 1537 cm−1; 1H NMR (500 MHz, CDCl3) δH
7.80−7.78 (m, 2H), 7.51 (tt, J = 7.3, 1.6 Hz, 1H), 7.45−7.41 (m, 2H),
6.75 (br s, 1H), 3.83 (t, J = 5.0 Hz, 2H), 3.63 (q, J = 5.2 Hz, 2H), 2.16
(br s, 1H); 13C NMR (126 MHz, CDCl3) δC 168.9, 134.3, 131.9, 128.8,
127.2, 62.6, 43.1; HRMS (ESI) m/z: [M + H]+ calcd for C9H12NO2
166.0863, found 166.0860.
1
mg, 96%): νmax (neat) 3412, 3220, 3066, 2928, 1623, 1558 cm−1; H
NMR (400 MHz, CDCl3) δH 7.57 (dd, J = 8.0, 1.1 Hz, 1H), 7.50 (dd, J
= 7.6, 1.8 Hz, 1H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.28−7.24 (m, 1H),
6.58 (br s, 1H), 3.82 (t, J = 4.8 Hz, 2H), 3.60 (q, J = 5.2 Hz, 2H), 2.70
(br s, 1H); 13C NMR (101 MHz, CDCl3) δC 168.8, 137.7, 133.5, 131.6,
129.6, 127.8, 119.5, 62.0, 42.9; HRMS (ESI) m/z: [M + Na]+ calcd for
C9H10BrNO2Na 265.9784, found 265.9784.
1-Benzyl-N-(2-hydroxyethyl)piperidine-4-carboxamide (12g). Yel-
low oil (245 mg, 66%): νmax (neat) 3437, 3233, 2922, 1651, 1599, 1537
cm−1; 1H NMR (400 MHz, DMSO) δH 7.71 (t, J = 5.5 Hz, 1H), 7.33−
7.26 (m, 4H), 7.25−7.21 (m, 1H), 4.62 (t, J = 5.5 Hz, 1H), 3.42 (s,
2H), 3.38−3.33 (m, 2H), 3.08 (q, J = 6.1 Hz, 2H), 2.79 (d, J = 11.5 Hz,
2H), 2.10−2.03 (m, 1H), 1.87 (td, J = 11.4, 3.0 Hz, 2H), 1.63−1.49 (m,
4H); 13C NMR (101 MHz, CDCl3): δC 176.5, 138.3, 129.3, 128.4,
127.3, 63.4, 62.4, 53.2, 43.5, 42.5, 29.1; HRMS (ESI) m/z: [M + H]+
calcd for C15H23N2O2 263.1754, found 263.1752.
General Procedure for Base-Catalyzed Amide Bond For-
mation. To an oven-dried Schlenk tube containing BEMP (41 μL, 0.14
mmol) and acetonitrile (700 μL) were added ester (1.42 mmol) and
amino alcohol (1.42 mmol). The reaction mixture was stirred at room
temperature or 40 °C for 15 h and then concentrated to a residue that
was purified by flash column chromatography (methanol/CH2Cl2). For
oxazolidinone synthesis, the ester was replaced with dimethyl carbonate
(350 μL, 4.26 mmol).
N-(3-Hydroxypropyl)-2-phenylacetamide (10a).29 White solid
(220 mg, 80%): νmax (neat) 3310, 3242, 3067, 2945, 2882, 1655,
1564 cm−1; 1H NMR (400 MHz, DMSO) δH 8.01 (t, J = 4.4 Hz, 1H),
7.31−7.19 (m, 5H), 4.42 (t, J = 4.8 Hz, 1H), 3.40−3.38 (m, 4H), 3.09
(q, J = 6.5 Hz, 2H), 1.54 (app. quin, J = 6.7 Hz, 2H); 13C NMR (101
MHz, DMSO) δC 170.0, 136.6, 128.9, 128.2, 126.3, 58.4, 42.4, 35.8,
32.4; HRMS (ESI) m/z: [M + Na]+ calcd for C11H15NO2Na 216.0995,
found 216.0991.
2-(3-Cyanophenoxy)-N-(2-hydroxyethyl)-2-(naphthalen-1-yl)-
acetamide (12h). Colorless oil (298 mg, 61%): νmax (neat) 3350, 3098,
2958, 2232, 1661, 1530, 1248 cm−1; 1H NMR (400 MHz, CDCl3) δH
8.30 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 12.5, 8.1 Hz, 2H), 7.66−7.56 (m,
3H), 7.52−7.43 (m, 2H), 7.34−7.23 (m, 2H), 7.22−7.10 (m, 1H),
7.01−6.91 (m, 1H), 6.28 (s, 1H), 3.70 (t, J = 5.1 Hz, 2H), 3.58 (s, 1H),
3.50 (q, J = 5.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δC 157.0, 156.9,
134.3, 131.4, 131.2, 130.9, 130.3, 129.3, 127.4, 126.5, 126.2, 125.5,
123.9, 123.6, 120.9, 120.0, 118.4, 113.7, 78.7, 66.5, 38.3; HRMS (ESI)
m/z: [M + H]+ calcd for C21H19N2O3 347.1390, found 347.1392.
N-(2-Hydroxyethyl)pyrazine-2-carboxamide (12j). White solid
N-(4-Hydroxybutyl)-2-phenylacetamide (10b).30 White solid (118
1
mg, 40%): νmax (neat) 3358, 3291, 2951, 1636, 1541 cm−1; H NMR
(400 MHz, DMSO) δH 8.01 (t, J = 5.0 Hz 1H), 7.31−7.18 (m, 5H),
4.38 (t, J = 5.2 Hz, 1H), 3.39−3.35 (m, 4H), 3.05−3.00 (m, 2H), 1.43−
1.37 (m, 4H); 13C NMR (101 MHz, DMSO) δC 169.8, 136.6, 128.9,
128.1, 126.2, 60.4, 42.4, 38.5, 29.8, 25.8; HRMS (ESI) m/z: [M + Na]+
calcd for C12H17NO2Na 230.1152, found 230.1146.
1
(161 mg, 68%): νmax (neat) 3410, 3261, 2940, 1666, 1564 cm−1; H
NMR (400 MHz, DMSO) δH 9.18 (d, J = 1.5 Hz, 1H), 8.87 (d, J = 2.5
Hz, 1H), 8.78 (t, J = 5.2 Hz, 1H), 8.73−8.72 (m, 1H), 4.81 (t, J = 5.6
Hz, 1H), 3.53 (q, J = 6.0 Hz, 2H), 3.39 (q, J = 6.1 Hz, 2H); 13C NMR
(101 MHz, DMSO) δC 162.8, 147.5, 144.7, 143.5, 143.3, 59.5, 41.6;
HRMS (ESI) m/z: [M + H]+ calcd for C7H10N3O2 168.0768, found
168.0765.
N-(2-Hydroxybenzyl)-2-phenylacetamide (10f). White solid (161
1
mg, 47%): νmax (neat) 3279, 3102, 2569, 1626, 1568 cm−1; H NMR
(400 MHz, CDCl3) δH 9.47 (br s, 1H), 7.41−7.35 (m, 3H), 7.29−7.25
(m, 3H), 7.10 (dd, J = 7.5, 1.7 Hz, 1H), 7.00 (dd, J = 8.1, 1.0 Hz, 1H),
6.91−6.86 (m, 2H), 4.35 (d, J = 6.5 Hz, 2H), 3.60 (s, 2H); 13C NMR
(101 MHz, CDCl3) δC 174.0, 156.0, 134.0, 130.9, 130.2, 129.7, 129.3,
127.9, 124.2, 120.0, 118.0, 43.1, 40.9; HRMS (ESI) m/z: [M + H]+
calcd for C15H16NO2 242.1176, found 242.1177.
2-Chloro-N-(3-hydroxypropyl)-6-methylpyrimidine-4-carboxa-
mide (12k). Yellow oil (261 mg, 80%): νmax (neat) 3365, 3101, 1671,
1
cm−1; H NMR (500 MHz, CDCl3) δH 8.12 (br s, 1H), 7.91 (s, 1H),
3.70 (t, J = 5.4 Hz, 2H), 3.64 (q, J = 6.4 Hz, 2H), 2.87 (br s, 1H), 2.64
(s, 3H), 1.87−1.82 (m, 2H); 13C NMR (126 MHz, CDCl3) δC 173.7,
162.8, 160.3, 158.8, 117.0, 59.6, 36.7, 32.3, 24.6; HRMS (ESI) m/z: [M
+ H]+ calcd for C9H13N3O2Cl 230.0961, found 230.0960.
N-(3-Hydroxypropyl)-6-methylnicotinamide (12l). White solid
(207 mg, 75%): νmax (neat) 3444, 3237, 2926, 2895, 1651, 1539
cm−1; 1H NMR (500 MHz, CDCl3) δH 8.85 (d, J = 2.1 Hz, 1H), 8.03
(dd, J = 8.1, 2.3 Hz, 1H), 7.44 (br s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 3.76
(t, J = 5.5 Hz, 2H), 3.62 (q, J = 5.9 Hz, 2H), 2.58 (s, 3H), 1.85−1.80
(m, 2H), 1H missing (exchangeable); 13C NMR (126 MHz, CDCl3) δC
166.5, 161.7, 147.4, 135.9, 127.6, 123.4, 60.6, 38.2, 31.8, 24.6; HRMS
(ESI) m/z: [M + Na]+ calcd for C10H14N2O2Na 217.0941, found
217.0945.
N-(2-Hydroxyethyl)-N-methyl-2-phenylacetamide (11a).31 Yellow
oil (249 mg, 91%): νmax (neat) 3339, 3129, 2900, 1641, 1500 cm−1; 1H
NMR (400 MHz, CDCl3) δH 7.36−7.30 (m, 2H), 7.28−7.25 (m, 3H),
3.82 (s, 0.73H, minor rotamer), 3.76−3.73 (m, 2.47H, major + minor
rotamers), 3.65 (t, J = 5.4 Hz, 0.75H, minor rotamer,), 3.55 (t, 1.28H, J
= 5.4 Hz, major rotamer,), 3.43 (t, J = 5.4 Hz, 0.84H, minor rotamer,)
3.32 (br s, 1H), 3.06 (s, 1.85H, major rotamer), 2.96 (s, 1.10H, minor
rotamer); 13C NMR (101 MHz, CDCl3, major rotamer) δC 172.9,
134.7, 128.9, 128.8, 126.9, 60.8, 51.3, 41.1, 37.2; 13C NMR (101 MHz,
CDCl3, minor rotamer) δC 172.3, 135.5, 129.0, 128.6, 126.8, 59.5, 52.4,
F
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The Journal of Organic Chemistry
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N-(2-Hydroxyethyl)-4H-1,2,4-triazole-3-carboxamide (12m).
White solid (62 mg, 28%): νmax (neat) 3406, 3273, 3102, 2982, 1644,
1563 cm−1; 1H NMR (400 MHz, DMSO) δH 8.43 (s, 1H), 4.78 (br s,
1H), 3.49 (t, J = 6.2 Hz, 2H), 3.34−3.30 (m, 3H), 1H missing
(exchangeable); 13C NMR (101 MHz, DMSO) δC 158.2, 147.0, 59.5,
41.4, 1C missing (coincident); HRMS (ESI) m/z: [M + H]+ calcd for
C5H9N4O2 157.0720, found 157.0718.
(coincident); HRMS (ESI) m/z: [M + H]+ calcd for C12H14BrClNO2
317.9891, found 317.9896; [α]D20 −50 (c 2.0, CHCl3).
(S,E)-1-(2-(Hydroxymethyl)pyrrolidin-1-yl)-3-phenylprop-2-en-1-
one (13b).32 Yellow oil (302 mg, 92%): νmax (neat) 3350, 2949, 2876,
1
1645, 1582, 1422 cm−1; H NMR (400 MHz, CDCl3) δH 7.63−7.56
(m, 1H), 7.45−7.42 (m, 2H), 7.31−7.20 (m, 3H), 6.90 (d, J = 15.2 Hz,
0.23H, minor rotamer), 6.66 (d, J = 15.2 Hz, 0.73H, major rotamer),
5.30 (br s, 1H), 4.23 (app. quin, J = 5.7 Hz, 0.75H major rotamer),
4.15−4.10 (m, 0.27H, minor rotamer), 3.61−3.47 (m, 4H, major +
minor rotamers), 1.98−1.86 (m, 2H, major + minor rotamers), 1.84−
1.76 (m, 1.2H, major rotamer), 1.69−1.62 (m, 0.78H, minor rotamer);
13C NMR (101 MHz, CDCl3, major rotamer) δC 166.6, 142.6, 134.8,
129.7, 128.7, 127.8, 118.3, 65.9, 60.8, 47.8, 27.8, 24.1; 13C NMR (101
MHz, CDCl3, minor rotamer) δC 165.3, 141.4, 135.1, 129.2, 128.5,
127.7, 119.1, 64.1, 58.9, 46.1, 28.2, 21.7; HRMS (ESI) m/z: [M + H]+
N-(2-Hydroxyethyl)-1-methyl-1H-1,2,4-triazole-5-carboxamide
(12n). White solid (227 mg, 94%): νmax (neat) 3237, 3101, 1671, 1580
1
cm−1; H NMR (400 MHz, CDCl3) δH 7.87 (br s, 1H), 7.82 (s, 1H),
4.25 (s, 3H), 3.83 (t, J = 5.2 Hz, 2H), 3.60 (q, J = 5.5 Hz, 2H), 3.01 (br
s, 1H); 13C NMR (101 MHz, CDCl3) δC 157.9, 149.5, 146.3, 61.6, 42.2,
38.5; HRMS (ESI) m/z: [M + Na]+ calcd for C6H10N4O2Na 193.0691,
found 193.0693.
N-(2-Hydroxyethyl)-1H-pyrrole-2-carboxamide (12o). Yellow oil
20
1
(201 mg, 92%): νmax (neat) 3277, 2940, 2878, 1607, 1560 cm−1; H
calcd for C14H18NO2 232.1332, found 232.1331; [α]D −39 (c 2.1,
MeOH).
NMR (400 MHz, DMSO) δH 11.41 (br s, 1H), 7.96 (t, J = 5.6 Hz, 1H),
6.83 (td, J = 2.7, 1.5 Hz, 1H), 6.76−6.74 (m, 1H), 6.06 (dt, J = 3.6, 2.4
Hz, 1H), 4.72 (br s, 1H), 3.47 (t, J = 6.3 Hz, 2H), 3.27 (q, J = 6.1 Hz,
2H); 13C NMR (101 MHz, DMSO) δC 160.9, 126.4, 121.2, 109.9,
108.5, 60.1, 41.4; HRMS (ESI) m/z: [M + Na]+ calcd for
C7H10N2O2Na 177.0632, found 177.0631.
(S)-(2-(Hydroxymethyl)pyrrolidin-1-yl)(1H-indol-5-yl)methanone
(13d). Colorless oil (197 mg, 57%): νmax (neat) 3318, 3211, 2963,
2891, 2846, 1629, 1554 cm−1; 1H NMR (400 MHz, DMSO) δH 11.25
(s, 1H), 7.72 (br s, 1H), 7.41−7.40 (m, 2H), 7.25−7.24 (m, 1H), 6.49
(t, J = 2.0 Hz, 1H), 4.81 (s, 1H), 4.18−4.08 (m, 1H), 3.68−3.59 (m,
1H), 3.52−3.49 (m, 2H), 3.42−3.38 (m, 1H), 1.98−1.87 (m, 3H), 1.66
(br s, 1H); 13C NMR (126 MHz, DMSO) δC 170.3, 136.3, 128.1, 126.7,
126.4, 120.7, 119.8, 110.8, 101.8, 61.8, 58.7, 50.5, 27.2, 24.7; HRMS
(ESI) m/z: [M + H]+ calcd for C14H17N2O2 245.1285, found 245.1284;
N-(2-Hydroxyethyl)pyrimidine-2-carboxamide (12p). White solid
(195 mg, 82%). Also prepared as follows: To a solution of pyrimidine-
2-carboxylic acid (176 mg, 1.42 mmol) and Et3N (395 μL, 2.84 mmol)
in CH2Cl2 (1 mL) were added HATU (648 mg, 1.7 mmol) and
ethanolamine (86 μL, 1.42 mmol). The reaction mixture was stirred at
room temperature for 16 h, washed with water and 2 M HCl, dried
(MgSO4), filtered, and then concentrated to a residue that was purified
by flash column chromatography (4% methanol/CH2Cl2) to afford the
title compound as a white solid (180 mg, 76%). νmax (neat) 3403, 3310,
2919, 1651, 1538 cm−1; 1H NMR (400 MHz, CDCl3) δH 8.85 (d, J =
4.8 Hz, 2H), 8.48 (br s, 1 H), 7.42 (t, J = 4.9 Hz, 1H), 3.87−3.85 (m,
2H), 3.68 (q, J = 5.8 Hz, 2H), 3.36 (br s, 1H); 13C NMR (101 MHz,
CDCl3) δC 163.3, 157.7, 157.6, 122.8, 62.0, 42.8, 1C missing
(coincident); HRMS (ESI) m/z: [M + H]+ calcd for C7H10N3O2
168.0768, found 168.0765.
N-(2-Hydroxyethyl)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carbox-
amide (12s). White solid (136 mg, 61%): νmax (neat) 3410, 3277, 3090,
2931, 1663, 1647, 1559 cm−1; 1H NMR (500 MHz, DMSO) δH 8.20 (t,
J = 4.8 Hz, 1H), 4.73 (br s, 1H), 4.02−4.00 (m, 1H), 3.42 (t, J = 6.0 Hz,
2H), 3.15 (q, J = 5.8 Hz, 2H), 2.60 (s, 3H), 2.26−2.15 (m, 3H), 1.81−
1.76 (m, 1H); 13C NMR (126 MHz, DMSO): δC 174.5, 171.1, 61.8,
59.7, 41.5, 29.3, 27.9, 22.5; HRMS (ESI) m/z: [M + H]+ calcd for
C8H15N2O3 187.1077, found 187.1075.
20
[α]D −139 (c 1.0, MeOH).
N-Benzyl-N-(2-hydroxyethyl)-2-phenylacetamide (13g). White
solid (371 mg, 97%): νmax (neat) 3399, 3333, 3063, 2934, 1624,
1
1489 cm−1; H NMR (400 MHz, CDCl3) δH 7.35−7.19 (m, 8H),
7.17−7.15 (m, 1H), 7.09 (d, J = 6.8 Hz, 1H), 4.62 (s, 0.73H, minor
rotamer), 4.58 (s, 1.27H, major rotamer), 3.86 (s, 0.77H, minor
rotamer), 3.72−3.67 (m, 2.41H, major rotamer), 3.59 (t, J = 5.4 Hz,
0.76H, minor rotamer), 3.53 (t, J = 5.0 Hz, 1.30H, major rotamer), 3.34
(t, J = 5.6 Hz, 0.71H, minor rotamer), 2.43 (br s, 1H); 13C NMR (101
MHz, CDCl3, major rotamer) δC 174.0, 136.4, 134.8, 129.2, 129.0,
128.8, 128.1, 127.2, 126.6, 62.3, 53.1, 49.4, 41.4; 13C NMR (101 MHz,
CDCl3, minor rotamer) δC 174.0, 137.9, 135.5, 129.1, 128.9, 128.7,
128.2, 127.6, 127.0, 60.3, 50.3, 48.8, 41.0; HRMS (ESI) m/z: [M + H]+
calcd for C17H20NO2 270.1489, found 270.1489.
5-(4-Bromophenyl)-N-(2-hydroxyethyl)-N,3-dimethylisoxazole-4-
carboxamide (13h). Colorless oil (433 mg, 90%): νmax (neat) 3399,
2934, 1612, 1398 cm−1; 1H NMR (400 MHz, CDCl3, major rotamer):
δH 7.64−7.55 (m, 4H), 3.85 (t, J = 5.4 Hz, 1.30H, major rotamer), 3.70
(s, 1.13H, major rotamer), 3.49 (t, J = 4.8 Hz, 0.64H minor rotamer),
3.10 (s, 1.03H, minor rotamer), 2.85 (s, 3H), 2.30 (s, 2H, major
rotamer), 2.27 (s, 0.98H, minor rotamer), 1H missing (exchangeable);
13C NMR (101 MHz, CDCl3, major rotamer) δC 164.9, 164.5, 159.1,
5-(4-Bromophenyl)-N-(2-hydroxyethyl)-3-methylisoxazole-4-car-
boxamide (12t). White solid (305 mg, 66%): νmax (neat) 3271, 3112,
1
2955, 1643, 1545 cm−1; H NMR (400 MHz, CDCl3) δH 7.70−7.67
132.6, 128.0, 125.7, 125.5, 111.4, 60.2, 50.1, 37.2, 10.4; 13C NMR (101
MHz, CDCl3, minor rotamer) δC 164.4, 164.1, 159.5, 132.5, 127.9,
125.8, 125.3, 111.8, 58.8, 52.8, 33.0, 10.3, 1C missing (overlapping
peaks); HRMS (ESI) m/z: [M + H]+ calcd for C14H16BrN2O3
339.0339, found 339.0336.
(m, 2H), 7.65−7.63 (m, 2H), 6.13 (br s, 1H), 3.78 (t, J = 5.0 Hz, 2H),
3.56 (q, J = 5.2 Hz, 2H), 2.46 (s, 3H), 1.96 (br s, 1H); 13C NMR (101
MHz, CDCl3) δC 167.1, 162.9, 160.0, 132.6, 129.6, 126.0, 125.7, 112.3,
61.9, 42.4, 11.2; HRMS (ESI) m/z: [M + H]+ calcd for C13H14BrN2O3
325.0182, found 325.0184.
N,N-Bis(2-hydroxyethyl)-2-phenylacetamide (13i).33 White solid
1
(279 mg, 81%): νmax (neat) 3329, 3204, 2903, 1601, 1479 cm−1; H
(S)-(4-Bromo-2-chlorophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)-
methanone (13a).15 A 2.5 g scale: To an oven-dried Schlenk tube
containing BEMP (290 μL, 1 mmol) and acetonitrile (5 mL) were
added methyl 4-bromo-2-chlorobenzoate (12.5 g, 10 mmol) and (S)-
(+)-2-(hydroxymethyl)pyrrolidine (987 μL, 10 mmol). The reaction
mixture was stirred at room temperature for 15 h and then
concentrated to a residue that was purified by flash column
chromatography (4% methanol/CH2Cl2) to afford the title compound
as a colorless oil (2.92 g, 92%): νmax (neat) 3389, 2949, 2876, 1612,
1581, 1425 cm−1; 1H NMR (500 MHz, CDCl3) δH 7.60 (d, J = 1.5 Hz,
1H), 7.48 (dd, J = 8.3, 1.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.36 (qd, J
= 7.3, 3.6 Hz, 1H), 3.82 (dd, J = 11.5, 3.0 Hz, 1H), 3.76 (dd, J = 11.8,
7.3 Hz, 1H), 3.27−3.26 (m, 2H), 2.20−2.15 (m, 1H), 1.92−1.87 (m,
1H), 1.86−1.77 (m, 1H), 1.74−1.67 (m, 1H), 1H missing
(exchangeable); 13C NMR (126 MHz, CDCl3) δC 168.3, 136.0,
132.7, 130.9, 128.8, 123.7, 66.8, 61.8, 49.6, 28.8, 24.7, 1C missing
NMR (500 MHz, DMSO) δH 7.74 (d, J = 8.0 Hz, 1H), 7.30−7.24 (m,
4H), 7.22−7.19 (m, 1H), 4.60 (t, J = 5.3 Hz, 2H), 3.72−3.66 (m, 1H),
3.43 (s, 2H), 3.40 (t, J = 5.3 Hz, 4H); 13C NMR (126 MHz, DMSO) δC
170.0, 136.6, 129.0, 128.1, 126.2, 60.1 52.9, 42.3; HRMS (ESI) m/z:
[M + Na]+ calcd for C11H15NO3Na 232.0944, found 232.0941.
N-(2-Hydroxy-2-methylpropyl)-4-(trifluoromethyl)benzamide
(13l). White solid (189 mg, 51%): νmax (neat) 3447, 3312, 2980, 1639,
1547 cm−1; 1H NMR (500 MHz, DMSO) δH 8.47 (t, J = 6.0 Hz, 1H),
8.05 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 4.54 (s, 1H), 3.27 (d,
J = 6.2 Hz, 2H), 1.11 (s, 6H); 13C NMR (126 MHz, DMSO) δC 165.6,
138.6, 131.0 (q, 2JCF = 32.2 Hz), 128.2, 125.2 (q, 3JCF = 3.2 Hz), 124.0
1
(q, JCF = 272.2 Hz), 69.8, 50.3, 27.4; HRMS (ESI) m/z: [M + Na]+
calcd for C12H14NO2F3Na 284.0869, found 284.0867.
(S)-4-Benzyloxazolidin-2-one (14a).25 White solid (171 mg, 68%):
1
νmax (neat) 3263, 2921, 1707 cm−1; H NMR (400 MHz, CDCl3) δH
G
dx.doi.org/10.1021/jo501929c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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7.35 (tt, J = 8.1, 1.8 Hz, 2H), 7.30 (dt, J = 5.1, 2.1 Hz, 1H), 7.20−7.17
(m, 2H), 5.19 (br s, 1H), 4.50−4.46 (m, 1H), 4.17 (dd, J = 8.5, 5.6 Hz,
1H), 4.13−4.06 (m, 1H), 2.93−2.84 (m, 2H); 13C NMR (126 MHz,
CDCl3) δC 159.4, 136.2, 129.2, 129.1, 127.5, 69.9, 54.0, 41.7; HRMS
(ESI) m/z: [M + H]+ calcd for C10H12NO2 178.0863, found 178.0858;
[α]D20 −60 (c 1.0, CHCl3), lit.34 [α]D20 −62 (c 1.0, CHCl3).
(5) For a review, see: El-Faham, A.; Albericio, F. Chem. Rev. 2011,
111, 6557−6602.
(6) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411−420.
(7) For a recent review, see: Lundberg, H.; Tinnis, F.; Selander, N.;
Adolfsson, H. Chem. Soc. Rev. 2014, 42, 2714−2742.
(8) Allen, C. L.; Chhatwal, A. R.; Williams, J. M. J. Chem. Commun.
2012, 48, 666−668.
(S)-4-Phenyloxazolidin-2-one (14b).35 White solid (153 mg, 66%):
1
νmax (neat) 3237, 3142, 1705 cm−1; H NMR (400 MHz, CDCl3 δH
7.44−7.33 (m, 5H), 6.12 (br s, 1H), 4.97 (t, J = 7.8 Hz, 1H), 4.74 (t, J =
8.7 Hz, 1H), 4.19 (dd, J = 8.6, 6.9 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δC 160.0, 139.7, 129.4, 129.0, 126.2, 72.7, 56.6; HRMS (ESI)
m/z: [M + Na]+ calcd for C9H9NO2Na 186.0521, found 186.0523;
[α]D20 +53 (c 2.0, CHCl3), lit36 [α]D20 +48 (c 2.0, CHCl3).
(9) Lundberg, H.; Tinnis, F.; Adolfsson, H. Synlett 2012, 23, 2201−
2204.
(10) Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.; Ohshima,
T. Org. Lett. 2014, 16, 2018−2021.
(S)-4-Isopropyloxazolidin-2-one (14c).34 White solid (154 mg,
84%): νmax (neat) 3253, 3153, 2958, 1721, 1472 cm−1; 1H NMR (500
MHz, CDCl3): δH 6.23 (br s, 1H), 4.45 (t, J = 8.6 Hz, 1H), 4.11 (dd, J =
8.7, 6.3 Hz, 1H), 3.64−3.59 (m, 1H), 1.74 (dq, J = 13.5, 6.8 Hz, 1H),
0.97 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δC 160.7, 68.8, 58.6, 32.9, 18.2, 17.8; HRMS (ESI) m/z: [M +
H]+ calcd for C6H12NO2 130.0863, found 130.0862; [α]D20 +6 (c 1.0,
(11) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed.
2008, 47, 2876−2879.
(12) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61,
4196−4197.
(13) Arnold, K.; Batsanov, A. S.; Davies, B.; Whiting, A. Green Chem.
2008, 10, 124−134.
(14) Tuccio, B.; Ferre, E.; Comeau, L. Tetrahedron Lett. 1991, 32,
2763−2764.
CHCl3), lit37 [α]D +8 (c 1.0, CHCl3).
20
Oxazolidin-2-one (14d).33 White solid (73 mg, 51%): νmax (neat)
3248, 2989, 2919, 1712, 1485 cm−1; 1H NMR (500 MHz, DMSO) δH
7.45 (br s, 1H), 4.30−4.27 (m, 2H), 3.46−3.42 (m, 2H); 13C NMR
(126 MHz, CDCl3) δC 161.2, 65.2, 40.8; HRMS (EI) m/z: [M]+ calcd
for C3H5NO2 87.0315, found 87.0316.
(15) Caldwell, N.; Jamieson, C.; Simpson, I.; Tuttle, T. Org. Lett.
2013, 15, 2506−2509.
(16) Carlson, R. Design and Optimization in Organic Synthesis;
Elsevier: Amsterdam, 1992; Chapter 2.
(17) Schwesinger, R. Chimia 1985, 39, 269.
(S)-Tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (14e).38 Yellow oil
(18) Armstrong, A.; Li, W. N,N′-Carbonyldiimidazole. Encyclopedia of
Reagents for Organic Synthesis; John Wiley & Sons: Hoboken, 2007.
(19) Anslyn, E. V.; Dougherty, D. A. Strain and Stability. In Modern
Physical Organic Chemistry; University Science: Sausalito, CA, 2006;
Chapter 2, pp 100−109.
1
(125 mg, 69%): νmax (neat): 2974, 2911, 1738, 1481 cm−1; H NMR
(400 MHz, CDCl3) δ 4.45 (dd, J = 8.9, 7.9 Hz, 1H), 4.10 (dd, J = 8.9,
3.6 Hz, 1H), 3.88−3.81 (m, 1H), 3.60−3.53 (m, 1H), 3.13−3.08 (m,
1H), 2.07−1.97 (m, 2H), 1.93−1.83 (m, 1H), 1.46−1.36 (m, 1H); 13C
NMR (101 MHz, CDCl3) δ 161.8, 67.8, 59.5, 45.8, 30.7, 25.7; HRMS
(ESI) m/z: [M + H]+ calcd for C6H10NO2 128.0706, found 128.0704;
[α]D20 −68 (c 2.3, MeOH).
(20) pKa values calculated by ACD
(21) Gleeson, M. P. J. Med. Chem. 2008, 51, 817−834.
(22) Mukherjee, S.; Pal, M. Curr. Med. Chem. 2013, 20, 4386−4410
and references cited therein..
(23) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397−4398.
(24) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127−2129.
(25) Mullen, G.; Napier, J.; Balestra, M.; DeCory, T.; Hale, G.; Macor,
J.; Mack, R.; Loch, J.; Wu, E.; Kover, A.; Verhoest, P.; Sampognaro, A.;
Phillips, E.; Zhu, Y.; Murray, R.; Griffith, R.; Blosser, J.; Gurley, D.;
Machulskis, A.; Zongrone, J.; Rosen, A.; Gordon, J. J. Med. Chem. 2000,
43, 4045−4050.
4-(Hydroxymethyl)oxazolidin-2-one (14f).39 Yellow oil (144 mg,
87%): νmax (neat): 3331, 3242, 2933, 2878, 1722, 1418 cm−1; 1H NMR
(500 MHz, DMSO) δ 7.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.30 (t, J =
8.6 Hz, 1H), 4.05 (dd, J = 8.5, 5.0 Hz, 1H), 3.78−3.71 (m, 1H), 3.37−
3.35 (m, 2H); 13C NMR (126 MHz, DMSO) δ 159.1, 64.4, 62.7, 53.2;
HRMS (ESI) m/z: [M + H]+ calcd for C4H8NO3 118.0499, found
118.0496.
ASSOCIATED CONTENT
■
S
(26) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77−80.
(27) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 6th ed.; Elsevier Inc.: Oxford, UK, 2009.
(28) Heller, S. T.; Fu, T.; Sarpong, R. Org. Lett. 2012, 14, 1970−1973.
(29) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453−2456.
(30) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465,
1027−1033.
* Supporting Information
Copies of spectroscopic data (1H and 13C NMR) for all
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: craig.jamieson@strath.ac.uk.
■
(31) Mahe, O.; Desroches, J.; Paquin, J.-F. Eur. J. Org. Chem. 2013,
4325−4331.
(32) De Sarkar, S.; Grimme, S.; Studer, A. J. Am. Chem. Soc. 2010, 132,
1190−1191.
Notes
The authors declare no competing financial interest.
(33) Gu, K.; Bi, L.; Zhao, M.; Wang, C.; Ju, J.; Peng, S. Bioorg. Med.
Chem. 2007, 15, 4775−4799.
ACKNOWLEDGMENTS
■
(34) Pridgen, L. N.; Prol, J., Jr. J. Org. Chem. 1989, 54, 3231−3233.
(35) Gabriele, B.; Salerno, G.; Brindisi, D.; Costa, M.; Chiusoli, G. P.
Org. Lett. 2000, 2, 625−627.
We thank AstraZeneca and the EPSRC for financial support of
this work. HRMS data were generated by the EPSRC National
Mass Spectrometry Service at the University of Swansea, UK.
(36) Xiong, H.; Grebe, T. M. R.; Mulder, J. A.; Hsung, R. P. Org.
Synth. 2005, 81, 147−156.
(37) Adams, H.; Collins, R. C.; Jones, S.; Warner, C. J. A. Org. Lett.
2011, 13, 6576−6579.
REFERENCES
■
(1) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471−479.
(2) Peptides, Synthesis, Structures and Applications; Gutte, B., Ed.;
Academic Press: San Diego, 1995.
(38) Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.-I.; Murahashi, S.-I.
Bull. Chem. Soc. Jpn. 1996, 69, 2079−2090.
(39) Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.; Griffin, D.;
Campbell, A. D. J. Am. Chem. Soc. 2006, 128, 2514−2515.
(3) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451−
3479.
(4) Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Angew.
Chem., Int. Ed. 2010, 49, 8082−8091.
H
dx.doi.org/10.1021/jo501929c | J. Org. Chem. XXXX, XXX, XXX−XXX