Interrupted aza-Wittig reactions using iminophosphoranes to synthesize 11C-carbonyls

Article abstract of DOI:10.1039/d1cc01016f

A direct CO2-fixation methodology couples structurally diverse iminophosphoranes with various nucleophiles to synthesize ureas, carbamates, thiocarbamates, and amides, and is amenable for 11C radiolabeling. This methodology is practical, as demonstrated by the synthesis of >35 products and isolation of the molecular imaging radiopharmaceuticals [11C]URB694 and [11C]glibenclamide. This journal is

Full text of DOI:10.1039/d1cc01016f

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Interrupted aza-Wittig reactions using
11
iminophosphoranes to synthesize C–carbonyls†
Cite this: Chem. Commun., 2021,
57, 5266
ab
ab
bc
Uzair S. Ismailani,
Benjamin H. Rotstein
Maxime Munch,
Braeden A. Mair
and
abc
Received 24th February 2021,
Accepted 26th April 2021
*
DOI: 10.1039/d1cc01016f
rsc.li/chemcomm
A direct CO2-fixation methodology couples structurally diverse technique has displayed improved utility for synthesizing
iminophosphoranes with various nucleophiles to synthesize ureas, asymmetrical ureas10 and also amides using either Grignard
carbamates, thiocarbamates, and amides, and is amenable for 11C reagents11 or organozinc coupling reactions,12 though high
radiolabeling. This methodology is practical, as demonstrated by mass loading of azo reagents and phosphines may complicate
the synthesis of 435 products and isolation of the molecular radiotracer purification. Each strategy requires careful control
imaging radiopharmaceuticals [11C]URB694 and [11C]glibenclamide. of temperature and reagent concentrations during sequential
reaction steps in order to prevent formation of complex mix-
Positron emission tomography (PET) is a molecular imaging tures of symmetrical byproducts and heterocycles.9 Iminopho-
modality used to evaluate biological processes in vivo with sphoranes have been shown to undergo the aza-Wittig reaction
short-lived radionuclides. PET radiopharmaceuticals are used directly with CO2 to produce isocyanates in high yields.13 In the
to diagnose metastatic and cardiovascular diseases, to detect context of 11C, the commercially available precursor N-(triphe-
biomarkers of neurodegeneration, and to probe molecular and nylphosphoranylidene)aniline (1a) was previously reported
functional mechanisms in living systems. Carbon-11 (11C, t1/2
=
to prepare acyclic 11C-ureas from [11C]CO2 in moderate radio-
20.4 min) is prized for isotopic labeling of biomolecules, and is chemical yields (RCYs).14 Del Vecchio et al. deployed o-azidoa-
routinely incorporated into PET imaging agents for both nilines and azido alcohols with dimethylphenylphosphine to
research and clinical applications.1 Currently, a lack of diverse synthesize cyclic ureas and carbamates in useful yields through
methods for directly incorporating [11C]CO2 into complex a proposed intramolecular Staudinger aza-Wittig sequence
molecules has limited its use.2 Consequently, [11C]CO2 is most (SAW, Scheme 1a) upon heating to 70 1C.15,16 An intermolecular
often converted into reactive secondary precursors such as variant of this reaction produced a linear carbamate in low RCY
[11C]CH3I or [11C]CH3OTf, which are accompanied by elongated at much higher temperature.
processing times and reductions in radiochemical yield due to
sub-quantitative conversions.3–6
We aimed to develop conditions that are high yielding and
selective for C–O, C–N, C–C, and C–S bond formation and
Isocyanates are valuable synthetic intermediates that can be would be amenable for one-pot [11C]CO2-fixation to prepare
readily converted into pharmaceutically-relevant functional
groups such as carbamates, ureas, and amides.7,8 Current
approaches to synthesizing 11C-isocyanates rely on stepwise
trapping of [11C]CO2 with amines, followed by dehydration
using POCl3 or Mitsunobu-type conditions.2,9,10 Importantly,
the former strategy displays poor tolerance towards anilines
and the highly acidic conditions pose challenges for maintain-
ing efficient trapping of [11C]CO2 in solution. The latter
a Department of Biochemistry, Microbiology and Immunology, University of Ottawa,
Canada. E-mail: benjamin.rotstein@uottawa.ca
b University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, Canada
c Department of Chemistry and Biomolecular Sciences, University of Ottawa,
Canada
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Synthetic approaches to iminophosphorane [11C]CO2-fixation.
d1cc01016f
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radiopharmaceuticals and novel tracer candidates. Through the DBU and phosphazene BEMP (2.6 equiv.), significantly increased
synthesis of functionalized iminophosphorane precursors, this the rate of formation of 4, concomitant with moderate impacts
approach would obviate the need for highly acidic POCl3, Mitsu- in yield (entries 9–10, Table S1, ESI†). These effects are likely due
nobu reagents, explosive azide precursors, and toxic phosphines to the increased availability of soluble CO2 complexes.17,18
used in current methodologies, enhancing the substrate versatility
We assessed the compatibility of the iminophosphorane-
and practicality of this method for good manufacturing CO2-fixation method with a diverse scope of nucleophiles
practices (GMP) environments (Scheme 1b). Herein, we describe (Scheme 2a). Under our developed conditions, carbamates
a versatile and efficient approach to carbonyl ligation using derived from benzyl, isopropyl, 4-methoxyphenethyl, and tert-
iminophosphorane-CO2-fixation coupled with intermolecular butyl alcohol were isolated in 83–94% yields (4–7). In contrast,
nucleophilic addition. This method is effective for synthesizing phenyl carbamates and thiocarbamates (8–10) required higher
acyclic products with stable isotopes under mild conditions and is nucleophile concentrations to achieve yields Z70%, likely due
suitable for automated synthesis and 11C radiolabeling.
to their propensity for elimination. Benzyl mercaptan also
At the outset, we focused on developing a nucleophilic proved to be a compatible nucleophile, forming the corres-
coupling strategy to iminophosphorane-CO2 fixation condi- ponding thiocarbamate 11 in 86% yield. Sterically hindered
tions using stable isotopes, since no such straightforward nucleophiles gave carbamate 7 (83%) and urea 12 (78%). We
procedure for this coupling has been reported.13 First, CO2 were gratified to find that amides such as 13 (82%) could be
was bubbled into a heated toluene solution containing (1a) accessed directly by carbon–carbon bond formation using
until consumption of the iminophosphorane, followed by the diethyl malonate. Despite this success, some nucleophiles were
addition of benzyl alcohol (2). Low yield of the desired product found to be incompatible with the interrupted aza-Wittig con-
4 (6%) was observed using stepwise addition (Table 1, entry 1). ditions, including Grignard reagents and phenylacetylene.
The observed major product was the symmetrical N,N0- However, several of our synthesized products (7–10, 12) stand
diphenylcarbodiimide (3), likely formed by a second aza- in as blocked isocyanates, and facilitate indirect nucleophilic
Wittig coupling reaction to the isocyanate intermediate. The substitution (Scheme 2b).19 In situ formed O-phenylcarbamate
ratio of 4 : 3 increased to 0.9 : 1 when the nucleophile was 8 was transformed to amides 14–16 in moderate-to-good yields
present from the beginning of the reaction (entry 3). Increasing based on 1a. Both direct and indirect nucleophilic substitu-
the concentration of 2 led to exclusive formation of 4 in 84% tions are robust, and further open the door to selective C–C
yield (entry 4). This suggests that short-lived free isocyanates bond formation using iminophosphoranes.
are formed in the presence of iminophosphoranes, subject to
We next investigated the scope of functionalized aryl imi-
two competing reaction pathways: aza-Wittig carbodiimide nophosphoranes synthesized by the Kirsanov reaction and
formation and carbamate formation. Thus, at high concentra- isolated by our modified general procedure (Scheme 2c, see
tions of an intercepting nucleophile, it is possible to selectively ESI† for details). First, CBz-protected products (17–21) were
divert the reaction towards intermolecular ligation. Carbamate isolated to determine sensitivity to electronic and steric
4 could be prepared and isolated in good yields from hydro- features of iminophosphoranes under the optimized condi-
carbon, ethereal, and polar solvents using similar conditions tions. Electron-rich arenes, aryl bromides, and ortho-
(entries 5–8). With our primary focus on establishing substitution (17–18, 21) were all well-tolerated in comparison
easily translatable conditions to 11C radiochemistry, we were with electron-deficient arenes (19–20). Alkyl iminophopho-
delighted to find that two common CO2 trapping bases, amidine sphoranes afforded products such as carbamate 22 (82%) and
blocked isocyanates 23–24 in good yields. The utility of this
method for biopharmaceuticals was assessed by targeting the
fatty acid amide hydrolase inhibitor URB694 (25), melatonin
Table 1 Optimization of reaction conditions
(26), and the oral multi-kinase inhibitor regorafenib (29).
Hydroquinone carbamate 25 was isolated as a mixture of
regioisomers in 60% yield.9 Indirect substitution using
phenol-blocked isocyanates yielded melatonin 26 (72%), phe-
Entry
Solvent
[2] (mM)
3 Yield (%)
4 Yield (%)
nylalanine derivative 27 (84%), and electron-deficient amide 28
(73%). Finally, the urea regorafenib 29 was synthesized first
by direct nucleophilic coupling, though indirect substitution
using an N-tert-butylmethylamine blocked isocyanate intermedi-
ate better facilitated purification of 29 in 71% overall yield.20
Satisfied with the iminophosphorane-CO2 nucleophilic cou-
pling methodology using stable isotopes, we were determined
to apply this method to 11C radiochemistry. Since [11C]CO2 is
the limiting reagent in these processes (typically o1 mmol),
reconsideration of reaction conditions to produce [11C]4 was
required (Table 2). First, we focused on the influence of the
concentration of 1a on product yield using high concentrations
1ab
2ab
3ac
4ac
5d
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
DMF
ACN
ACN
ACN
100
150
100
250
250
250
250
250
250
250
77
77
42
0
0
0
0
0
0
0
6
6
36
84
70
72
75
78
84
70
6d
7d
8d
9de
10df
a
b
UPLC/MS yields; 110 1C. Nucleophile added after iminophosphorane
c
d
consumption. Nucleophile added at t = 0. Conditions: 2 (0.625 mmol),
solvent (2.5 mL), 85 1C; then 1 (100 mM, 2.5 mL) added over 1 h. Reaction
time: 2 h. Isolated yields. DBU (2.6 equiv). BEMP (2.6 equiv).
e
f
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Scheme 2 For Extended Functionality – Reaction Scope. a Conditions: 1 (0.25 mmol), R2-XH (2.5 equiv.), DBU (2.6 equiv.), ACN (2.5 mL), reflux; isolated
yields. b PhOH (10 equiv.), R3-MgX (20 equiv.) or PhCCH (12 equiv.), THF. c R2-XH (10 equiv.), LHMDS (0.99 equiv.), THF. See ESI† for detailed procedures.
of DBU and benzyl alcohol in ACN (entry 1). We noted a low derived products of 1a include labeled urea [11C]30 in 88% RCY,
13% RCY with these initial conditions, mainly due to a large and blocked isocyanate [11C]12 in 32% RCY. Using benzyl
excess of unreacted [11C]CO2. Increasing the concentration of iminophosphorane, O-benzyl carbamate [11C]31 was formed
1a (entries 2–3) led to maximum 32% RCY and reducing the in 64% yield. By substituting DABCO for DBU, O-aryl carbamate
concentration of DBU to 100 mM enhanced the selectivity [11C]32 (26%), 5-methoxytryptamine carbamate [11C]33 (84%),
toward [11C]4 (entry 4–5). Increasing the reaction temperature and thiocarbamate [11C]34 (93%) could be radiolabeled, with
in DMF to 100 1C resulted in 65% RCY (entries 6–7). Finally, TE ranging from 53–83%. We suspect that mildly basic condi-
increasing the concentration of nucleophile 2 further improved tions and higher nucleophile concentrations improve the yields
the selectivity of [11C]4, leading to a 91% RCY (entries 7–9). of 32–34 due to their sensitivity towards elimination.21 From
Trapping efficiencies (TE) of [11C]CO2 during the optimization tert-butyl iminophosphorane, N-hydroxysuccinimide-derived
of [11C]4 were all greater than 90%.
[11C]23 (99%) was also radiolabeled.
Structurally diverse iminophosphoranes were also used to
To further demonstrate the practicality of this technique,
radiolabel compounds using this procedure (Scheme 3). Aniline [11C]35, an experimental antiarrhythmic compound containing
the b-glucocerebrosidase activating moiety N-methyl-N-(2-
phenoxyethyl)amine, was isolated using a fully automated
Table 2 Radiochemical optimization
method (see ESI†).22,23 [11C]35 was labeled with 99% RCY
starting from 15.7 GBq of [11C]CO2, and obtained in an isolated
yield of 33% ꢀ 10.6% (2.7 ꢀ 0.4 GBq) within 22 min of [11C]CO2
delivery. The fatty acid amide hydrolase inhibitor [11C]URB694
([11C]25, [11C]CURB), used in clinical research to investigate
Entry
T (1C)
[1a] (mM)
[2] (mM)
[DBU] (mM)
RCYa (%)
psychiatric illnesses and alcohol use disorder, was prepared
from cyclohexyliminophosphorane in 96% ꢀ 2% RCY (2 : 3
1
2
3
4
65
65
65
65
65
7
70
100
70
70
70
70
70
70
200
200
200
200
200
200
200
600
1200
200
200
200
150
100
100
100
100
100
13
32
29
39
56
62
65
78
91
regioselectivity).24,25 From 25.9 GBq of
[
11C]CO2, 1.9
ꢀ
0.7 GBq of [11C]CURB was obtained as the major isomer in
99% radiochemical purity, with an isolated yield of 13% ꢀ 2%,
and molar activity of 69 ꢀ 37 GBqꢁmmolꢂ1 within 17 min from
[11C]CO2 delivery. Lastly, the sulfonylurea glibenclamide, cur-
rently used in the treatment of diabetes mellitus type 2 and
shown to reduce tissue damage in preclinical models of CNS
injuries, was synthesized with 75% ꢀ 14% RCY.26 [11C]Gliben-
clamide ([11C]36) is a substrate for organic anion-transporting
5
6b
7b
8b
9b
65
100
100
100
a
Radiochemical yield calculated by relative integration of radioHPLC
chromatograms, see ESI for details; average of n Z 2; entry 9 n = 6;
trapping efficiency Z 90%. DMF solvent.
b
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Conflicts of interest
There are no conflicts to declare.
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