Rhodium-Catalyzed Addition of Organozinc Iodides to Carbon-11 Isocyanates

Article abstract of DOI:10.1021/acs.orglett.0c00729

Amides were prepared using rhodium-catalyzed coupling of organozinc iodides and carbon-11 (¹¹C, t_1/2 = 20.4 min) isocyanates. Nonradioactive isocyanates and sp³ or sp² organozinc iodides generated amides in yields of 13%-87%. Incorporation of cyclotron-produced [¹¹C]CO₂ into ¹¹C-amide products proceeded in yields of 5%-99%. The synthetic utility of the methodology was demonstrated through the isolation of [¹¹C]N-(4-fluorophenyl)-4-methoxybenzamide ([¹¹C]6g) with a molar activity of 267 GBq μmol^-1 and 12% radiochemical yield in 21 min from the beginning of synthesis.

Full text of DOI:10.1021/acs.orglett.0c00729

pubs.acs.org/OrgLett
Letter
Rhodium-Catalyzed Addition of Organozinc Iodides to Carbon-11
Isocyanates
Braeden A. Mair, Moustafa H. Fouad, Uzair S. Ismailani, Maxime Munch, and Benjamin H. Rotstein*
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ABSTRACT: Amides were prepared using rhodium-catalyzed coupling of organozinc iodides and carbon-11 (11C, t1/2 = 20.4 min)
isocyanates. Nonradioactive isocyanates and sp3 or sp2 organozinc iodides generated amides in yields of 13%−87%. Incorporation of
cyclotron-produced [11C]CO2 into 11C-amide products proceeded in yields of 5%−99%. The synthetic utility of the methodology
was demonstrated through the isolation of [11C]N-(4-fluorophenyl)-4-methoxybenzamide ([11C]6g) with a molar activity of 267
GBq μmol−1 and 12% radiochemical yield in 21 min from the beginning of synthesis.
this obstacle but still require multistep activation to
ositron emission tomography (PET) is a noninvasive
Pnuclear medicine technology used for in vivo molecular intermediate acid chlorides, which themselves often require
purification.8−11 Alternative synthetic approaches have been
developed for 11C-carbonylation with [11C]carbon monoxide,
using either preformed arylpalladium complexes12 or alkyl
iodide coupling mediated by nickel.13 While these options are
effective in synthesizing complex amide products, only a few
laboratories prepare [11C]CO.14
imaging. Carbon-11 (11C, t1/2 = 20.4 min), which is a short-
lived PET isotope, is commonly used for labeling small
molecules and peptide radiotracer candidates, although its
utility is limited by the availability of chemical methodologies
suitable for its incorporation.1,2 Therefore, the abundance and
diversity of organic frameworks in radiopharmaceuticals calls
for continued development of novel 11C-labeling techniques to
satisfy imaging needs.
Amides are a prodigious functional group in synthetic and
biological molecules and amide bond formation is among the
most commonly used and important reactions in drug
discovery.3,4 However, many powerful synthetic strategies
using stable isotopes prove wasteful, impractical, and/or
ineffective when applied to carbon-11 radiochemistry. Conven-
tional approaches to amide synthesis focus on acylation of an
amine, and, indeed, the same can be accomplished using low-
molecular-weight 11C-acid chlorides.5 Still, 11C can only be
produced in single carbon units, most frequently as [11C]CO2,
and therefore more general methods directed at rapid
formation of both the C−N and the C−C bonds of amides
are needed to leverage existing medicinal chemistry approaches
for radiotracer development.
An alternative strategy toward 11C-amides is to begin with
11C−N formation, for example, through an 11C-isocyanate or
11C-carbamyl chloride intermediate (Figure 1), followed by
derivatization with a carbon-based nucleophile. Indeed,
Grignard reagents have recently been successfully deployed
in such a context for preparing 11C-amides, although their
elevated reactivity and limited functional group compatibility
may restrict practical applications in radiopharmaceutical
Figure 1. Strategies for stable isotope and carbon-11 amide synthesis.
Received: February 25, 2020
Established methods for the preparation of 11C-amides use
amines and 11C-carboxylic acids, the latter prepared from
organolithium or Grignard reagents and [11C]CO2. These
syntheses require great care, because of the use of reagents that
can readily react with atmospheric CO2, resulting in lower
molar activity products. Recent advances using less-reactive
organometallic precursors for [11C]CO2 fixation6,7 overcome
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Org. Lett. XXXX, XXX, XXX−XXX
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Letter
synthesis.15 Organozinc halides represent another class of
organometallics offering greater stability toward many chemical
moieties. Previously, a limited scope of amides had been
prepared from allyl and propargyl organozinc halides and aryl
isocyanates.16 However, direct addition of alkyl and benzyl
organozinc halides to isocyanates did not yield amides, but
rather carbamates and urea byproducts. Foreseeing a potential
direct route to 11C-amides that could prove useful in PET
radiochemistry, we set out to evaluate conditions redirecting
organozinc halide reactivity with isocyanates toward selective
C−N bond formation.
Scheme 1. Substrate Scope with Respect to Arylzinc
Iodides
a
We herein report a transition-metal-catalyzed coupling of
organozinc iodides and isocyanates to produce a diverse scope
of amides. This approach is effective with in-situ-prepared 11C-
isocyanates to generate 11C-amides in suitable yields for
radiotracer development.
Arylzinc iodides were the initial target for reaction discovery.
First, the addition of phenylzinc iodide (1a) to phenyl
isocyanate (2a) to produce benzanilide (3a) was used to
develop coupling conditions (see Table 1). Only a trace
Table 1. Optimization of Arylzinc Iodide Reaction
a
Conditions
b
entry
solvent
catalyst
yield 3a [%]
1
2
3
4
THF
THF
THF
THF
THF
Et2O
ACN
DMSO
THF
−
<5
<5
Pd(OAc)2
c
[Rh(Cl)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
75, 71
c
78, 74
d
a
5
68
30
62
19
13
Reaction conditions: 1 (2 equiv, 0.4 mmol), 2 (1 equiv, 0.2 mmol),
[Rh(OH)(cod)]2 (2.5 mol %, 0.005 mmol), THF (2 mL), rt, 30 min,
under Ar.
6
7
8
e
9
a
(3e). One or more ortho-methyl substituents were well-
tolerated on isocyanates with only slightly decreased product
yields (3f and 3g). Benzyl, phenethyl, isopropyl and allyl
isocyanates could also be used to form amides 3i−3l.
Functionalized electron-rich arylzinc iodides were superior in
reactivity, improving nucleophilicity of the reagent, as with 3m,
compared to those with electron-withdrawing groups such as
products 3n and 3o.
Unless otherwise specified, reactions were performed with 1a (0.4
mmol), 2a (0.2 mmol), and 2.5 mol % catalyst in solvent (2 mL) at
room temperature. Yields were calculated using calibrated HPLC-
UV peak integration. Isolated yields. 50 °C. Reversed order of
addition.
b
c
d
e
amount of product was detected in the absence of a catalyst
(Table 1, entry 1). While Pd(OAc)2 proved ineffective for
improvement of conversion, [Rh(Cl)(cod)]2 successfully
yielded 3a in 71% yield (Table 1, entries 2 and 3).
[Rh(OH)(cod)]2 also demonstrated strong selectivity and
conversion with a yield of 74% (Table 1, entry 4). The yields
were not further improved by the use of heat, which led to a
slight increase in the formation of symmetrical diphenyl urea
(Table 1, entry 5). More polar solvents could also facilitate the
reaction (Table 1, entries 6−8), which would prove important
for radiochemical applications. A significant decrease in yield
upon reversing the order of reactant addition indicated the
importance of premixing the isocyanate with the catalyst before
introducing organozinc iodides (Table 1, entry 9).
The scope of the reaction was evaluated for arylzinc iodides
under the optimized conditions with various isocyanates (see
Scheme 1). Electron-deficient aryl isocyanates reacted
smoothly, affording the products 3b−3d in good yields.
Conversely, coupling with electron-rich 2-methoxyphenyl
isocyanate (2e) was accompanied by a reduced isolated yield
Alkyl organozinc iodides were prepared17 and successfully
coupled with isocyanates under similar conditions to prepare
C-alkyl amides, with longer reaction times required for
complete conversion. Notably, addition of [Rh(OH)(cod)]2
suppresses the previously reported carbamate formation.16
Various additives were evaluated for their effect on reaction
progress. Conversions decreased with the addition of triethyl-
amine,18 while phenol,19 DBU, and azo compounds were well-
tolerated (see the Electronic Supporting Information (ESI)),
suggesting the possibility of a one-pot 11C-amide synthesis
from [11C]CO2.
Similar steric and electronic trends could be observed with
alkylzinc iodides as with arylzinc iodides (see Scheme 2): more
electron-poor isocyanates proceeded with useful product yields
(4b and 4c) and ortho-substituents were moderately tolerated
(4e−4g), while electron-donating groups or alkyl isocyanates
fared worse (4e, 4i, 4j). Generally, products of ethylzinc iodide
were isolated in higher yields, compared to those prepared
B
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Letter
a
a
Scheme 2. Scope, with Respect to Alkylzinc Iodides
Table 2. Optimization for [11C]Acetanilide Synthesis
trapping
efficiency, TE
[%]
radiochemical
b
TE ×
RCY [%]
entry
base
yield, RCY [%]
1 (n = 2)
2
BEMP
BEMP
BEMP
DBU
DBU
DBU
DBU
DBU
DBU
DBU
99
1
15
1
20
4
7
74
72
77
27
8
c
75
60
5
11
74
78
d
3
e
f
4
>99
92
95
5
6 (n = 4)
3
81
2
g
7
8
68
68
90
89
40
12
81
80
h
i
9
10
73
71
j
a
Reaction conditions: (i) 5a (22.90 μmol), base (35.50 μmol), ACN
(500 μL), <2 min; (ii) PBu3 (45.80 μmol) and DBAD (45.80 μmol),
b
a
ACN (100 μL), 1 min; and (iii) 15 min. Calculated from integration
Reaction conditions: 1 (3 equiv, 0.6 mmol), 2 (1 equiv, 0.2 mmol),
[Rh(OH)(cod)]2 (2.5 mol %, 0.005 mmol), THF (2 mL), rt, 24 h,
under Ar.
c
d
e
of radioHPLC signal. DMSO. DMF. Coupling performed for 10
f
g
h
i
min. [Rh(Cl)(cod)]2 used as a catalyst. 50 °C. 0 °C. 2.0 equiv
DBU. 2.5 equiv DBU.
j
from methylzinc iodide, although functionality trends were
maintained throughout (for the full zinc iodide reaction scope,
including additional compounds, see the ESI).
a
Scheme 3. Carbon-11 Substrate Scope
Satisfied with this characterization of rhodium-catalyzed
organozinc iodide coupling with stable isotope isocyanates, the
findings provided a framework to develop a method for 11C
chemistry. Less reactive methylzinc iodide was selected for
optimization, aiming toward [11C]acetanilide due to its
relevance as a parent compound to metabolic paracetamol,
one of the most commonly used analgesics.20
Initial trials using a POCl3-induced dehydration procedure
for the synthesis of 11C-isocyanates21,22 proved incompatible
with the coupling conditions. Dehydration using Mitsunobu
reagents23,24 (tributyl phosphine and di-tert-butyl azodicarbox-
ylate, DBAD) in acetonitrile provided more reliable access to
[11C]phenyl isocyanate and was also compatible with the
subsequent rhodium-catalyzed coupling with methylzinc iodide
(Table 2, entries 1−3). DBU, which is a base more commonly
used with Mitsunobu dehydration, provided a substantial
increase to both the trapping efficiency (TE) and radio-
chemical yield (RCY) (Table 2, entries 4−6). Various amounts
of DBU were used to evaluate stoichiometric effect on the
reaction: 1.5 equiv yielded the best results for trapping and
conversion (Table 2, entries 6, 9, and 10).
With an optimized procedure in hand, a series of biologically
relevant compounds were labeled with 11C using this technique
(Scheme 3). Isocyanates were prepared in situ using an
automated 11C synthesis system before being routed to a
secondary reactor containing the rhodium catalyst. The
coupling reaction commenced with the addition of organozinc
iodide (0.3 mL, 3.3−9.8 equiv), then was reacted for 10−15
min before aqueous quenching and radioHPLC analysis. Peak
integration was performed in order to derive radiochemical
yields and product identities were confirmed by coinjection
with nonradioactive standards of each compound. The method
ensures reliable trapping conditions while also leading to
moderate to strong radiochemical purity and yield. Many
compounds were prepared, including the biologically relevant
tert-butyl protected [11C]N-acetyl glutamic acid ([11C]6d), the
a
See the ESI for general procedure (P5). Standard error given for all
reactions.
agrochemical [11C]propanil ([11C]6e), and a pharmaceutically
relevant [11C]acetanilide ([11C]4k).
Amide [11C]6g was selected for further isolation to
demonstrate the utility of this labeling technique. A fully
automated method was implemented (see the ESI) with a total
time of 21 min from delivery of [11C]CO2 to end of
semipreparative HPLC purification (C18, aqueous acetonitrile
mobile phase). The decay-corrected radiochemical yield was
C
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Letter
12% from [11C]CO2 delivery with a molar activity of 267 GBq
μmol−1 (see Scheme 4).
Notes
The authors declare no competing financial interest.
Scheme 4. Automated Synthesis and Isolation of Amide
ACKNOWLEDGMENTS
a
[11C]6g
■
Financial and infrastructure support for this work were
provided by the University of Ottawa Heart Institute
(UOHI), and the Natural Sciences and Engineering Research
Council of Canada (NSERC, RGPIN-2017-06167), the
Canada Foundation for Innovation (CFI, 36848), and the
Ontario Ministry for Research, Innovation and Science (ER17-
13-119). B.A.M. was supported by the BioTalent Student
Work-Integrated Learning Program. The authors are grateful
to Dr. Tayebeh Hadizad and Daniel Duan (UOHI PET
Radiochemistry Core) for isotope production, and Prof. Andre
Beauchemin (University of Ottawa) for helpful discussions.
a
See the ESI for details.
́
In conclusion, we have developed a transition-metal-
catalyzed synthesis of amides that can be translated for use
with 11C. Organozinc iodides and isocyanates can be coupled
using rhodium catalysis to synthesize a wide array of amide
products under mild reaction conditions and with fast
synthesis times. 11C-Amide products can be derived in suitable
yields and fully automated for practical radiotracer synthesis.
This method will represent a new strategy for 11C-labeling of
biologically relevant amides.
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Authors
Braeden A. Mair − Departments of Chemistry and Biomolecular
Sciences, University of Ottawa, Ottawa, Ontario, Canada K1H
8M5; University of Ottawa Heart Institute, Ottawa, Ontario,
Canada K1Y 4W7
Moustafa H. Fouad − Departments of Biochemistry,
Microbiology and Immunology, University of Ottawa, Ottawa,
Ontario, Canada K1H 8M5; University of Ottawa Heart
Institute, Ottawa, Ontario, Canada K1Y 4W7
Uzair S. Ismailani − Departments of Biochemistry, Microbiology
and Immunology, University of Ottawa, Ottawa, Ontario,
Canada K1H 8M5; University of Ottawa Heart Institute,
Ottawa, Ontario, Canada K1Y 4W7
Maxime Munch − Departments of Biochemistry, Microbiology
and Immunology, University of Ottawa, Ottawa, Ontario,
Canada K1H 8M5; University of Ottawa Heart Institute,
Ottawa, Ontario, Canada K1Y 4W7
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