Alkali carbonate effects on N-(2-hydroxyethyl)urea cyclization: Application to a 2-imidazolidinone scale-up

Article abstract of DOI:10.1002/jhet.1648

An imidazolidinone intermediate (3) used in the synthesis of novel HIV-entry inhibitors was prepared on multihundred gram scales in four steps and 40% overall yield. The penultimate step in the synthesis involved regioselective N-cyclization of N-(2-hydroxylethyl)urea (11) by in situ activation of the terminal hydroxyl group with p-TsCl in the presence of base. The ratio of N-cyclized to O-cyclized products followed a group IA periodic trend relative to the alkali carbonate base employed. The use of Cs₂CO₃ as base effected the desired N-cyclization with a high degree of regiocontrol (>98%).

Full text of DOI:10.1002/jhet.1648

July 2013
Alkali Carbonate Effects on N-(2-Hydroxyethyl)urea Cyclization:
863
Application to a 2-Imidazolidinone Scale-Up
*
Istvan Kaldor, Timothy Spitzer, Maosheng Duan, Wieslaw M. Kazmierski, and Eric E. Boros
GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709
*
E-mail: eric.e.boros@gsk.com
Received November 10, 2011
DOI 10.1002/jhet.1648
Published online 1 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
An imidazolidinone intermediate (3) used in the synthesis of novel HIV-entry inhibitors was prepared on
multihundred gram scales in four steps and 40% overall yield. The penultimate step in the synthesis involved
regioselective N-cyclization of N-(2-hydroxylethyl)urea (11) by in situ activation of the terminal hydroxyl
group with p-TsCl in the presence of base. The ratio of N-cyclized to O-cyclized products followed a group
IA periodic trend relative to the alkali carbonate base employed. The use of Cs2CO3 as base effected the
desired N-cyclization with a high degree of regiocontrol (>98%).
J. Heterocyclic Chem., 50, 863 (2013).
INTRODUCTION
achieved with excess t-BuOK and subsequent activation of
the hydroxyl group (in situ) by addition of p-TsCl [13].
We recently required 200 g of the imidazolidinone 3
for use in lead optimization and scale-up work targeting
novel CCR5 receptor antagonists of general structure 4
(Scheme 1) [17].
A scalable synthesis of 3 by a regioselective N-cyclization
pathway similar to eq. 1a was subsequently developed. In the
course of this work, an interesting trend in selectivity and
reactivity for N-cyclization versus O-cyclization was
discovered by in situ activation of the hydroxyl group
with p-TsCl in the presence of alkali carbonate bases.
The use of DBU to facilitate the desired N-cyclization
was also evaluated, and the results of these studies are
described herein.
Imidazolidinone rings (1) are found in a wide array of
useful organic compounds including chiral auxiliaries
[1,2], antifungals [3,4], BACE-1 inhibitors [5], 5-HT2C
[6], NMDA [7] and CCR5 [8] receptor antagonists, and
androgen receptor modulators [9]. One of the more direct
routes to these compounds involves cyclization of N-(2-
hydroxyethyl)ureas (eq. 1a). These reactions are generally
accomplished by converting the hydroxyl substituent
to a suitable leaving group (either stepwise or in situ)
and subsequent cyclization (often in the presence of base)
[1–3,7,9–14]. Mitsunobu conditions (e.g., DEAD, PPh3)
are also utilized for this transformation [15,16]. In many
instances, selective N-cyclization by these methods is
not straightforward, and oxazolidines (2) resulting from
O-cyclization are common by-products (eq. 1b).
RESULTS AND DISCUSSION
The needed N-(2-hydroxyethyl)urea intermediate was
synthesized from (R)-amino alcohol 5 by the convergent route
illustrated in Schemes 2 and 3. Treating 5 with N-BOC-
protected ketopiperidine 6 and sodium triacetoxyborohydride
(STAB-H) in AcOH/CH2Cl2 afforded the desired reductive
amination product 7, which was used without purification.
In a separate pot (Scheme 3), methyl 2,4-difluoro-5-
aminobenzoate (8) was treated with CDI (1 equiv.) in
CH2Cl2. The symmetrical urea 9 (a minor by-product)
precipitated from the reaction mixture and was removed
by filtration. The CH2Cl2 filtrate containing the presumed
An early example of a regiocontrolled N-cyclization of this
type involved synthesis of N,N0-diphenyl-2-imidazolidinone
(1: R═Ph) by heating N-(2-hydroxyethyl)urea with ethyl
phosphorodichloridate (0.5 equiv.) and treatment of the
resulting intermediate with sodium ethoxide [11]. More
recently, selective N-cyclizations along these lines were
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I. Kaldor, T. Spitzer, M. Duan, W. M. Kazmierski, and E. E. Boros
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Scheme 1
Although complete removal of the DIAD by-product
was not achieved, mass spectra for the two products
revealed identical molecular weights (m/z 516, M + 1),
and their HMBC spectra confirmed the structural assign-
ments for imidazolidinone 12 and oxazolidine 13 shown
in Figure 1.
As expected, the ring oxygen of the oxazolidine (13)
produced a significant downfield shift in resonances for
the ring methylene carbon and protons (13C NMR: d = 72.7
1
ppm/ H NMR: d = 4.65, 4.10 ppm) compared with the
1
corresponding nuclei in 12 (13C NMR: d = 53.0 ppm/ H
NMR: d = 4.18, 3.50 ppm).
N-acyl imidazole 10 [18,19] was treated with aminol 7 and
stirred overnight to afford the desired N-(2-hydroxyethyl)
urea 11, which was isolated by flash chromatography
(318g, 60% overall yield).
Cyclization of 11 was initially investigated under
Mitsunobu conditions (eq. 2). Treating a THF solution of
11 and PPh3 (1.2 equiv.) with DIAD (1.2 equiv.) (0ꢀC to
RT) produced equal amounts of two products (12 and 13),
which were separated by silica-gel chromatography.
Following the Mitsunobu result, we turned our attention
to one-pot cyclizations analogous to the published
t-BuOK/p-TsCl procedure [13]; however, the electron-
withdrawing influence of the N-aryl substituent prompted
us to evaluate reagent bases milder than alkoxides (eq. 3).
In a typical probe experiment, a solution of p-TsCl
(1.1 equiv.) in CH3CN was added dropwise to a cold
stirred mixture of 11 (ca. 0.3 mmol) and base (2–4 equiv.)
in CH3CN. The reaction mixture was left to warm to RT
and stirred overnight. Results from these experiments are
displayed in Table 1 (entries 1–5).
Scheme 2
With the exception of Experiment 2, all cyclization
reactions went to completion. Percentage ratios of product
isomers were determined by integration of the multiplet for
the aromatic proton ortho to the methyl ester group (1H
NMR, CDCl3). The use of DBU as base gave almost exclu-
sively the desired imidazolidinone (12) (Table 1, entry 1).
With Na2CO3, the reaction was very slow (ca. 95% complete
after 10 days). In this case, the major product was the
undesired oxazolidine 13 accompanied by imidazolidinone
12 and unreacted 11. With K2CO3, Rb2CO3, and Cs2CO3,
the reactions went to completion and revealed an interesting
trend in cyclization regiochemistry. As illustrated in Table 1,
the percentage of N-cyclized product (12) increased
with respect to the alkali carbonate employed in the order
Scheme 3
Figure 1. Selected 13C (and 1H) NMR chemical shifts (d ppm) of 12 and
13 (DMSO-d6, HMBC).
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N-(2-Hydroxyethyl)urea Cyclization
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Table 1
Effects of DBU and alkali carbonates on N-cyclization versus O-cyclization of 11 with p-TsCl.
Experiment no.a
Base (equiv.)
12:13b
Mixing timec
Reaction temperature
1
2
3
4
DBU (2.3)
>98:2
10:90d
70:30
80:20
>98:2
>98:2
overnight
10 days
overnight
overnight
overnight
2 h
ꢁ10ꢀC to RT
0ꢀC to RT
Na2CO3 (4)
K2CO3 (4)
Rb2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
ꢁ10ꢀC to RT
ꢁ10ꢀC to RT
ꢁ10ꢀC to RT
ꢁ10ꢀC to 7ꢀC
5
6e
ap-TsCl (1.1 equiv.) in CH3CN added to a cold mixture of 11 and base in CH3CN.
bDetermined by 1H NMR.
cNot indicative of reaction rate.
d5% unreacted 11.
e0.6 mol scale.
Na+ < K+ < Rb+ < Cs+. In fact, the Cs2CO3 method gave
minimal O-cyclized product (similar to DBU) and was
subsequently found to effect complete cyclization within
2 h below 7ꢀC (Table 1, entry 6).
not ruled out. With stronger bases (e.g., Cs2CO3, DBU),
N-deprotonation of 15 is likely during cyclization leading
to the desired imidazolidinone product (12). The Cs2CO3/
p-TsCl cyclization conditions were selected for scale-up
(rather than DBU/p-TsCl) because the inorganic carbonate
base simplified the aqueous work-up (MTBE/water) and
afforded a cleaner product.
It is interesting to note that one of the fastest reactions
(with Cs2CO3) gave the highest percentage of N-cyclized
product, whereas the slowest reaction (with Na2CO3)
produced the greatest amount of O-cyclized isomer. This
trend in reactivity for the alkali carbonates is perhaps best
explained by base strength and solubility. Indeed, Cs2CO3
is the most organic soluble and strongest of the four alkali
carbonate bases evaluated [20] and is particularly effective
at N-alkylation of carbamates [21] and indoles [22].
Potential cyclization pathways are illustrated in Scheme 4.
Tosylate 15 is a likely intermediate and may be formed by a
“transfer activation” mechanism [13] (e.g., 11!14!15). In-
terestingly, the intermediacy of 15 was not obvious by HPLC
or LCMS, suggesting that its cyclization is not rate-limiting.
With weak bases (e.g., Na2CO3), O-cyclization of 15 may
occur without base assistance followed by deprotonation of
the oxazolidinium species (13•TsOH)ꢁ similar to a mecha-
nism proposed for O-cyclization of g-haloamides [23].
Direct O-cyclization of 14 through intermediate 16 is also
The largest scale ring closure performed was on 318 g
(ca. 0.6 mol) of 11. On this scale, the reaction mixture
was kept below ꢁ3ꢀC during the p-TsCl addition (mildly
exothermic with ca. -15ꢀC external cooling bath) and
maintained below +7ꢀC for 2 h following the addition at
which point the reaction was complete. Proton NMR
analysis of a worked-up aliquot showed a product mixture
identical to that observed for smaller scale runs. Because
in our hands, the physical properties of 12 (a rigid,
white foam) were not amenable to crystallization, we were
induced to carry the crude imidazolidinone 12 directly into
the ester hydrolysis stage, which afforded the crystalline
carboxylic acid 3 (eq. 4). Thus, following work-up of the
cyclized product (12), the MTBE layer was exchanged
for THF, and addition of LiOH, water, and MeOH effected
clean hydrolysis of the methyl ester. Work-up followed by
a single recrystallization from EtOH afforded pure 3 in
65% yield from 11 (40% overall yield from 5).
Scheme 4
In conclusion, a scalable synthesis of imidazolidinone 3
was accomplished on 200 g scale in 40% overall yield. A
key step in the synthesis involved selective N-cyclization
of 11 in the presence of base by in situ activation of the
hydroxyl group with p-TsCl. A remarkable progression in
the regioselectivity (N-cyclization versus O-cyclization)
was observed for this reaction with alkali carbonates. The
use of Cs2CO3 and p-TsCl gave predominantly N-cyclized
product and produced complete cyclization within 2 h below
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I. Kaldor, T. Spitzer, M. Duan, W. M. Kazmierski, and E. E. Boros
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(br, 2H), 3.50 (dd, 1H, J = 8.5, 6.4 Hz), 3.56 (m, 1H), 3.78
(br, 1H), 3.85 (s, 3H), 3.93 (br, 1H), 4.18 (t, 1H, J = 9.0 Hz), 4.92
(dd, 1H, J = 8.9, 6.4 Hz), 7.34 (t, 1H, J = 7.3 Hz), 7.40 (t, 2H,
J = 7.3Hz), 7.48 (d, 2H, J = 7.3 Hz), 7.52 (t, 1H, J = 10.8 Hz), 8.08
ambient temperature. On the other hand, Na2CO3/p-TsCl
produced the slowest reaction (>10d at RT) and the highest
percentage of O-cyclized isomer (13). The medicinal–
chemical synthesis and structure–activity relationships of
novel CCR5 receptor antagonists of general scructure 4 are
described elsewhere [17].
1
(t, 1H, J = 8.3 Hz); H NMR (400 MHz, CDCl3) d 1.12 (br, 1H),
1.35 (s, 9H), 1.49 (br d, 1H, J = 12Hz), 1.69 (br d, 1H, J = 12 Hz),
1.83 (ddd, 1H, J = 24, 12, 4 Hz), 2.53 (m, 1H), 2.62 (m, 1H), 3.54
(dd, 1H, J = 8.6, 6.2 Hz), 3.74 (m, 1H), 3.86 (s, 3H), 3.91
(br, 1H), 4.10 (br, 1H), 4.12 (t, 1H, J = 9 Hz), 4.72 (dd, 1H,
J = 9.2, 6.2 Hz), 6.89 (t, 1H, J = 10.5Hz), 7.38–7.28 (m, 5H), 8.09
(t, 1H, J = 8 Hz); ES MS (positive mode): m/z 516 (M+ 1).
EXPERIMENTAL
(R)-tert-Butyl-4-((2-hydroxy-1-phenylethyl)amino) piperidine-
(R,Z)-tert-Butyl 4-(2-((2,4-difluoro-5-(methoxycarbonyl)-phenyl)
imino)-4-phenyloxazolidin-3-yl)piperidine-1-carboxylate
(13). 1H NMR (500 MHz, DMSO-d6) d 1.07 (ddd, 1H, J = 24.8,
12.6, 4.4 Hz), 1.32 (s, 9H), 1.57 (br d, 1H, J = 12.5Hz), 1.75–1.82
(m, 2H), 2.64 (br, 2H), 3.82 (s, 3H), 3.72–3.86 (br, 2H), 3.95
(br, 1H), 4.09 (dd, 1H, J = 8.5, 5.0 Hz), 4.64 (t, 1H, J = 8.5 Hz),
5.05 (dd, 1H, J = 8.2, 5.0 Hz), 7.29 (t, 1H, J = 10.4 Hz), 7.35
1-carboxylate (7).
STAB-H (300 g, 1.41 mol) was added in
portions over 40 min to a stirred mixture of amino alcohol 5
(150 g, 1.09 mol), ketopiperidine 6 (200g, 1.00 mol), acetic acid
(180 g, 3.00 mol), and CH2Cl2 (2L) while maintaining the
reaction temperature below 10ꢀC. The mixture was allowed to
warm to ambient temperature and stirred overnight. The mixture
was washed with 10% NaHCO3 solution (3 ꢂ 2 L) to ensure
complete removal of acetic acid, dried over MgSO4, filtered, and
concentrated to afford 7 as a white solid: (312g, 97% crude
yield). This material was used without further purification: 1H
NMR (400 MHz, CDCl3) d 1.23 (m, 2H), 1.41 (s, 9H), 1.61
(m, 1H), 1.87 (m, 1H), 2.10 (br, 2H), 2.53 (m, 1H), 2.69 (m, 2H),
3.43 (dd, 1H, J = 10.5, 9.0 Hz), 3.64 (dd, 1H, J = 10.5, 4.5 Hz),
3.88 (dd, 1H, J = 9.0, 4.5 Hz), 3.94 (br m, 2H), 7.22–7.28 (m, 3H),
7.30–7.36 (m, 2H).
1
(m, 1H), 7.37–7.44 (m, 4H), 7.57 (t, 1H, J = 8.2 Hz); H NMR
(400 MHz, CDCl3) d 1.06 (br, 1H), 1.35 (s, 9H), 1.59 (br d, 1H,
J= 12 Hz), 1.75 (ddd, 1H, J= 24, 12, 4 Hz), 1.86 (br d, 1H,
J= 11 Hz), 2.57 (m, 1H), 2.69 (m, 1H), 3.85 (s, 3H), 3.93 (m, 2H),
4.06 (m, 1H), 4.12 (br, 1H), 4.53 (t, 1H, J = 8.4 Hz), 4.76 (dd, 1H,
J= 8.2, 5.1 Hz), 6.80 (t, 1H, J=10.3Hz), 7.38–7.26 (m, 5H), 7.67
(dd, 1H, J= 9.0, 7.8 Hz); ES MS (positive mode): m/z 516 (M + 1).
(R)-5-(3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2-oxo-4-
phenylimidazolidin-1-yl)-2,4-difluorobenzoic acid (3).
A
(R)-tert-Butyl 4-(3-(2,4-difluoro-5-(methoxycarbonyl) phenyl)-
1-(2-hydroxy-1-phenylethyl)ureido)piperidine-1-carboxylate
(11). A solution of aniline 8 (187 g, 1.00 mol) and CDI (162 g,
1.00 mol) in CH2Cl2 (1 L) was stirred for 2 h at RT. The residual
urea by product 9 was removed by filtration, and the filtrate was
combined with compound 7 (304 g, 0.95 mol) and stirred overnight
at RT. The reaction mixture was concentrated by rotovap, and the
crude material was purified by flash chromatography (column
details: 1.5kg silica gel/10cm diameter/37cm length) eluting first
with CH2Cl2 and then with 1:1 CH2Cl2/EtOAc to afford the
desired product (11) as a white foam (318 g, 60%): 1H NMR
(400 MHz, CDCl3) d 1.41 (s, 9H), 1.59 (m, 1H), 1.71–1.93
(m, 3H), 2.48–2.83 (m, 3H), 3.86 (s, 3H), 3.98–4.33 (m, 4H), 4.46
(m, 1H), 4.85 (m, 1H), 6.75 (t, 1H, J= 10.3 Hz), 7.26–7.43
(m, 5H), 7.94 (br s, 1H), 8.47 (t, 1H, J = 8.5 Hz); ES MS (negative
mode): m/z 532 (M–H)ꢁ; Anal. Calcd for C27H33F2N3O6•(0.25
H2O): C, 60.27; H, 6.28; N, 7.81. Found: C, 60.26; H, 6.22; N, 7.75.
Mitsunobu Cyclization of 11. DIAD (121 mg, 0.6 mmol)
was added to an ice-cold solution of the N-(2-hydroxyethyl)
urea 11 (267 mg, 0.5 mmol) and PPh3 (157 mg, 0.6 mmol) in
THF. The reaction was allowed to warm to RT and was
concentrated in vacuo. The crude mixture was purified by
flash chromatography on silica gel (0–100% EtOAc/hexanes
gradient), which afforded fractions of each separated isomer (12
and 13) accompanied by lesser amounts of DIAD related by-
product. 1H NMR resonances for the DIAD by-product were
solution of 11 (318 g, 0.60 mol) in CH3CN (2 L) was charged with
Cs2CO3 (780 g, 2.39 mol), and the mixture was stirred for 10 min
at RT and then cooled to ꢁ11ꢀC. A solution of p-TsCl (125 g,
0.66mol) in CH3CN (700 mL) was added over 30min while
maintaining the internal temperature below ꢁ3ꢀC. The reaction
mixture was stirred at 0–7ꢀC for 2 h, diluted with water, and
extracted with MTBE (3.5 L). The organic phase was stirred with
10% Na2CO3 for 30min, and the layers were separated. The
MTBE phase was dried over MgSO4, filtered, and concentrated,
chasing with MeOH to remove residual CH3CN. The resulting
crude imidazolidinone 12 was dissolved in THF (1L), and a
solution of LiOH•H2O (40 g, 0.95mol) in water (430mL) was
added with stirring followed by MeOH (500 mL). The reaction
mixture was stirred at RT for 45min and then acidified to pH 3–4
with 0.6 N HCl (1.6 L) while maintaining the reaction mixture at
or near ambient temperature with external cooling. The mixture
was maintained at 8ꢀC for 1 h, and the crude product was
collected by filtration and recrystallized from hot EtOH (4 L). The
desired product (3) was obtained as a white crystalline solid
(195 g, 65%): mp 227–229ꢀC (decomp.); 1H NMR (400MHz,
DMSO-d6) d 1.03 (m, 1H), 1.29 (s, 9H), 1.43 (m, 1H), 1.58
(m, 1H), 1.77 (m, 1H), 2.56 (br m, 2H), 3.46 (dd, 1H, J = 6.7,
8.8 Hz), 3.53 (m, 1H), 3.74 (m, 1H), 3.90 (m, 1H), 4.14 (t, 1H,
J = 8.8Hz), 4.89 (dd, 1H, J = 8.8, 6.3 Hz), 7.31 (t, 1H, J = 7.5Hz),
7.37 (t, 2H, J = 7.1 Hz), 7.41–7.48 (m, 3H), 8.01 (t, 1H,
J = 8.35 Hz), 13.41 (br s, 1H); 13C NMR (100MHz, DMSO-d6)
d 28.63 (s, 3C), 29.50 (1C), 30.41 (1C), 43.43 (br, 1C), 43.99 (br,
1C), 52.57 (s, 1C), 54.04 (s, 1C), 56.34 (s, 1C), 79.26 (s, 1C),
106.93 (t, 1C, JCF = 26 Hz), 116.46 (br d, 1C, JCF = 12Hz),
124.75 (br d, 1C, JCF = 11Hz), 127.68 (s, 2C), 128.93 (s, 1C),
129.47 (s, 2C), 130.68 (s, 1C), 142.40 (s, 1C), 154.37 (s, 1C),
157.80 (s, 1C), 160.16 (dd, 1C, JCF = 258, 12Hz), 159.30 (dd, 1C,
JCF = 258, 12Hz), 164.64 (d, 1C, JCF = 4 Hz); ES MS (negative
mode): m/z 500 (M–H)ꢁ; Anal. Calcd for C26H29F2N3O5•(0.36
H2O): C, 61.47; H, 5.90; N, 8.27. Found: C, 61.47; H, 5.70; N, 8.14.
as follows: 1H NMR (500 MHz, DMSO-d6)
d 1.17 ppm
(d), 4.76 ppm (m), and 8.86 ppm (br s). This impurity was
not detected by LCMS (DAD detector). Proton NMR and LCMS
data for the two major cyclized products are provided in the following.
(R)-tert-Butyl 4-(3-(2,4-difluoro-5-(methoxycarbonyl)-phenyl)-
2-oxo-5-phenylimidazolidin-1-yl)piperidine-1-carboxylate
(12). 1H NMR (500 MHz, DMSO-d6) d 1.06 (ddd, 1H, J = 24.8,
12.6, 4.4 Hz), 1.32 (s, 9H), 1.46 (br d, 1H, J = 12Hz), 1.62 (br
d, 1H, J = 12Hz), 1.80 (ddd, 1H, J = 24.8, 12.6, 4.4 Hz), 2.61
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet