Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

Article abstract of DOI:10.1039/d1sc02049h

C(sp³)-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp³)-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, andN-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.

Full text of DOI:10.1039/d1sc02049h

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Benzylic C–H isocyanation/amine coupling
sequence enabling high-throughput synthesis of
Cite this: Chem. Sci., 2021, 12, 10380
pharmaceutically relevant ureas†
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Sung-Eun Suh, ‡a Leah E. Nkulu,a Shishi Lin,b Shane W. Krska
b
a
*
and Shannon S. Stahl
C(sp3)–H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however,
such methods are often constrained by practical limitations. The present study outlines a C(sp3)–H
isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in
high-throughput format. The operationally simple C–H isocyanation method shows high site selectivity
and good functional group tolerance, and uses commercially available catalyst components and
reagents [CuOAc, 2,20-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide].
The isocyanate products may be used without isolation or purification in a subsequent coupling step
with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template
for implementation of C–H functionalization/cross-coupling in drug discovery.
Received 12th April 2021
Accepted 28th June 2021
DOI: 10.1039/d1sc02049h
rsc.li/chemical-science
Introduction
Synthetic methods that join two fragments derived from
abundant molecular building blocks, such as amide coupling
and Pd-catalyzed cross-coupling, are the most widely used in
drug-discovery.1–5 Implementation of these methods using
high-throughput experimentation (HTE) enables rapid creation
of diverse complex molecules for biological screening.6,7 Reac-
tions capable of using C(sp3)–H bonds as sites for cross-
coupling would be very appealing in this context.8,9 In order to
nd broad utility, such methods should (1) use the C–H
coupling partner as the limiting reagent, (2) exhibit high and
predictable site selectivity, (3) show broad functional group
tolerance, (4) use readily available catalysts and reagents, and
(5) be compatible with HTE methods.
Benzylic ureas are common motifs in FDA-approved drugs
and bioactive targets in medicinal chemistry (Fig. 1A),10–16 and
aromatic compounds with (hetero)benzylic C(sp3)–H bonds are
ubiquitous potential precursors to these structures. Recog-
nizing that ureas are readily accessed via coupling of amines
and organic isocyanates,17 two C(sp3)–H functionalization/
cross-coupling strategies were considered to access benzylic
aDepartment of Chemistry, University of Wisconsin-Madison, 1101 University Avenue,
Madison, Wisconsin 53706, USA. E-mail: stahl@chem.wsic.edu
bChemistry Capabilities for Accelerating Therapeutics, Merck & Co., Inc., 2000
Galloping Hill Road, Kenilworth, New Jersey 07033, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc02049h
Fig.
1
Copper-catalyzed benzylic C(sp3)–H isocyanation/amine
coupling. (A) Drug candidates embedding benzylic urea. (B) Two
possible one-pot synthetic approaches toward ureas from benzylic
C–H substrates. (C) Strategy for high-throughput synthesis of ureas.
NFSI,
N-fluorobenzenesulfonimide;
BiOx,
2,20-bis(oxazoline);
‡ Present address: Department of Chemistry, Ajou University, Suwon 16499,
Korea.
TMSNCO, (trimethylsilyl)isocyanate.
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ureas (Fig. 1B). A C–H amination/isocyanate coupling sequence reagent. Several mechanistic features of these reactions merit
(Fig. 1B, bottom) would leverage C–H amination methods to consideration. CuI-mediated activation of NSFI is proposed to
prepare a benzylic amine intermediate;18–25 however, these generate an N-centered radical (cNSI) that promotes hydrogen-
methods use ammonia surrogates (e.g., azide, sulfonamides) atom transfer (HAT), and the resulting benzylic radical
that require an additional step to obtain the amine. Moreover, undergoes oxidative functionalization (Fig. 2A, top cycle). The
the small number of commercially available organic isocyanates imidyl radical generated in this process can alternatively react
(Fig. 1B, right) limits the number of structures that could be with a second equivalent of CuI, “wasting” the imidyl radical
readily accessed. These factors complicate the use of HTE and and consuming CuI, which is needed for activation of NFSI
limit the synthetic scope and utility.26 The alternative sequence, (dashed gray pathway in Fig. 2A). Recent studies show that this
involving C–H isocyanation/amine coupling (Fig. 1B, top) offers deleterious side-reaction can be offset by including a mild
important advantages. This route leverages the vast number of sacricial reductant, such as a dialkylphosphite, in the reaction.
commercially available amines (Fig. 1B, right) and affords the This additive serves as a “redox buffer” to rescue catalytic
desired structures in only two steps. On the other hand, C(sp3)– activity via in situ regeneration of CuI (Fig. 2A, green portion of
H isocyanation methods have much less precedent.
bottom cycle).35–37
Existing C(sp3)–H isocyanation methods27,28 lack the features
A second mechanistic feature involves radical functionali-
necessary for medicinal chemistry applications. The rst zation, which can proceed by several different pathways. CuI can
precedent, reported by Hill and coworkers in 1983, used initiate radical-chain uorination of C–H bonds36,37,40–43 with
MnIII(TPP)NCO (TPP
¼
tetraphenylporphyrin) with iodo- NFSI, but Cu/NFSI methods more commonly promote oxidative
sylbenzene (PhIO) as the oxidant and sodium cyanate as the coupling of C–H bonds with nucleophilic reaction partners (Nu
coupling partner. This reaction provided important proof-of- ¼ CN, N3, OR, Ar, among others). The mechanism of coupling
concept, but the reaction was only demonstrated with cyclo- can vary and depends on the coupling partner (Fig. 2B(i)–(iii)).
hexane, used as a cosolvent in CH2Cl2, and afforded the Cy-NCO For example, enantioselective benzylic cyanation has been
product in only 7% yield with respect to PhIO. Groves and demonstrated, and mechanistic data support radical addition
coworkers signicantly improved upon this method using to CuII followed by reductive elimination from a benzyl–CuIII
Mn(TMP)F (TMP ¼ tetramesitylporphyrin) as the catalyst. While
this method employs C–H substrates as the limiting reagent
and affords isocyanate products in useful yields (ꢀ40–60%), the
complex protocols involved in catalyst preparation and the
isocyanation reaction limit the utility of the method. For
example, each reaction must be monitored by GC-MS to discern
appropriate timing for 9–18 sequential additions of the PhIO
oxidant and 3–6 additions of trimethylsilyl isocyanate
(TMSNCO) over the course of the reaction.
In light of the above considerations, we sought an
isocyanation/amine coupling protocol that combines opera-
tional simplicity with broad substrate scope to access diverse
synthetic libraries (Fig. 1C). The isocyanation/coupling
sequence outlined herein meets key criteria for use in medic-
inal chemistry, including use of the C–H substrate as the
limiting reagent, predictable benzylic site selectivity, no
requirement for isolation/purication of the reactivity isocya-
nate intermediate, compatibility with HTE methods, and
exclusive use of commercially available catalysts and reagents.
These methods demonstrate the use of (hetero)benzylic C–H
bonds as latent functional groups that may be engaged in cross-
coupling reactions and, more generally, provide a framework
for further development of C–H functionalization/coupling
methods that could nd utility in medicinal chemistry.
Results and discussion
Mechanistic considerations and reaction optimization
Cu-catalyzed radical-relay reactions that use N-uo-
robenzenesulfonimide (NFSI) as the oxidant have expanded
rapidly in recent years19,29–39 and offered a possible strategy to
Fig. 2 Mechanistic features of copper-catalyzed benzylic C(sp3)–H
isocyanation with N-fluorobenzenesulfonimide (NFSI). (A) Catalytic
cycles for formation of C–NCO bond and regeneration of copper(I). (B)
Possible mechanisms for benzylic radical functionalization in Cu/NFSI
achieve C–H isocyanation as these methods oen support
oxidative coupling with the C–H substrate as the limiting systems.
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intermediate (Fig. 2B(i)).30 Azidation affords racemic products, fragment of NFSI (9%). Other potential side products, such as
even with the same chiral ligands used for cyanation. Experi- those with C–OiPr, C]O, and C–F fragments, were not identi-
mental and computational data implicate a radical-polar ed. The remaining mass balance is attributed to the high
crossover mechanism, involving a benzyl cation intermediate reactivity of organic isocyanates, which are susceptible to
(Fig. 2B(iii)), but radical addition to the distal N-atom of a CuII- various side reactions.17 The lack of cyanate (i.e., the C–OCN)
bound azide is also possible (Fig. 2B(ii)).19 C–H etherication product formation is consistent with the reported instability of
with alcohol coupling partners affords racemic products, and this isomer and ability of cyanates to isomerize spontaneously
mechanistic studies support a radical-polar crossover mecha- into isocyanates.28,44,45 Racemic products were formed, even
nism (Fig. 2B(iii)).35
when using chiral bis(oxazoline) ligands L2 and L3 (see Fig. S1
With these mechanistic considerations in mind, screening of the ESI†). Thorough mechanistic studies were not pursued;
efforts were initiated to identify effective conditions for benzylic however, this observation and the similarity between isocyanate
C–H isocyanation. TMSNCO was selected as the source of and azide is consistent with radical-polar crossover pathway
isocyanate because the affinity of the TMS group for uoride (Fig. 2B(iii)) involving oxidation of the benzylic radical to afford
provides a driving force for isocyanate transfer to the copper(II) a benzylic cation intermediate.
center, where it could undergo coupling with the benzylic
radical. 1-Bromo-4-ethylbenzene (1a), which incorporates an
aryl bromide fragment suitable for subsequent elaboration, was
Synthetic scope of benzylic isocyanation
selected as the benzylic substrate. Relevant optimization data is The conditions identied for the preparation of 2a were then
summarized in Table 1, with additional details provided in the evaluated with a number of other benzylic substrates (Fig. 3).
ESI (see Tables S1–S10†). A solvent screen with 10 mol% cop- Given the aforementioned instability of isocyanates, only two of
per(I) acetate and 2,20-bis(oxazoline) L1 (entries 1–4) revealed the isocyanate intermediates were isolated and fully character-
a moderate yield of the benzyl isocyanate 2a from the reaction in ized (2t and 2u, see ESI†), in order to validate the in situ 1H NMR
acetonitrile (36%). Varying the ligand identity (L1–L4, entries 4– yields obtained with the other substrates. In the other cases, the
7) did not improve the yields (26–30%, see Table S4† for addi- isocyanation reactions were conducted in parallel, and the
tional ligands). Notable improvement in C–H isocyanation was crude reaction mixtures were then added to neat m-anisidine
observed upon adding di(isopropyl)phosphite [(iPrO)2P(O)H] as (5.0 equiv.) under N2, without any intermediate work-up. The
a redox buffer (entries 8–11). Optimal yield of 2a was achieved urea products (3a–3w) obtained from this protocol were isolated
with 0.5 equiv. (iPrO)2P(O)H (56% yield). The substrate is almost and fully characterized. Analysis of the data in Fig. 3 shows that
fully consumed in the reaction, with the sole identied the majority of benzylic substrates afford the desired isocyanate
byproduct arising from C–N coupling with the sulfonimide in yields of 40–60%, with the subsequent urea formation
proceeding in 60–99% yields.
Effective C–H substrates include relatively simple unsub-
stituted or para-substituted ethylbenzene derivatives (1a–1g), 1-
ethylnaphthalene (1h), and diphenylmethane (1p), although
Table 1 Reaction optimization dataa
isocyanation of the electron-decient and electron-rich
substrates 4-CN and 2-OMe ethylbenzene led to lower yields
(24% and 34%; results provided in Table S11,† together with
other less successful substrates). Reactions of substrates having
both tertiary aliphatic and benzylic C–H bonds exclusively gave
benzylic isocyanate products (2i–2k), with none of the corre-
sponding tertiary product. Fused 6- and 5-membered ring cyclic
substrates tetralin and indane showed good reactivity (2l and
2m), and only mono-isocyanation was observed with bibenzyl
(2n) and chroman (2o). Isocyanation was achieved at hetero-
benzylic C–H sites of nitrogen heterocycles (2q and 2r), in
addition to benzylic sites in several complex molecules (2s–2w).
The precursor of canagliozin46 having a thiophene hetero-
benzylic C–H site afforded 2s (61% yield), and both celestolide47
and nematal 105 (ref. 48) gave their respective C–H isocyanation
products, 2t and 2u, in 66% yield. 1t was selected for a testing
on larger preparative scale (5.0 mmol). Conversion to isocyanate
intermediate 2t and trapping with m-anisidine proceeded in
75% and 79% yields, respectively, affording 1.2 g of urea 3t (55%
yield over two steps). The precursor of dronedarone,49 with
a benzofuran scaffold, afforded the corresponding product 2v in
37% yield. The tetrahydroquinoline-embedded GnRH antago-
nist50 precursor was functionalized at the benzylic site furthest
Entry
Ligand
Solvent
Additive (mol%)
Yieldb (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
Benzene
CH2Cl2
CH3NO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
—
—
—
—
—
—
—
0
7
15
36
30c
26c
28
39
42
39
56
(iPrO)2P(O)H (40)
(iPrO)2P(O)H (50)
(iPrO)2P(O)H (60)
(iPrO)2P(O)H (50)
9
10
11d
a
0.4 mmol 1a. b NMR yield, ext. std. ¼ mesitylene. c no e.e. d 2.0 mol%
CuOAc/L1, 3.0 eq. TMSNCO, 2.5 eq. NFSI, 0.5 eq. (iPrO)2P(O)H, 0.12 M
CH3CN, 30 ꢁC, 2 h.
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Fig. 3 Scope of alkylarene for in situ benzylic C–H isocyanation and urea formation. a Substrate (0.4 mmol). b NMR yield, ext. std. ¼ mesitylene. c
CuOAc (10 mol%), L1 (10 mol%) at 30 ꢁC for 20 h. d CuOAc (6.0 mol%), L1 (6.0 mol%) at 40 ꢁC for 20 h. e Standard condition for 2 h. f Standard
g
condition at 25 ꢁC for 2 h. CuOAc (6.0 mol%), L1 (6.0 mol%) at 30 ꢁC for 20 h.
from the nitrogen (2w, 33% yield). Collectively, this set of and amides, carbamate, sulfone, and sulfonamides, in addition
substrates shows that the isocyanation method is applicable to to fused/non-fused and saturated/unsaturated heteroaromatic
a broad cross-section of pharmaceutically relevant core frag- rings. Three C–H building blocks, including the canagliozin
ments containing (hetero)benzylic C–H bonds.
precursor (1s), celestolide (1t), and nematal 105 (1u), were then
subjected to the sequential protocol (Fig. 4C, le). Each C–H
substrate was converted to the isocyanate on 1.3 mmol scale,
High-throughput synthesis of ureas via sequential C–H
isocyanation/amine coupling
1
aer which the reactions were analyzed by H NMR spectros-
copy to determine the yield of isocyanate. Then, aliquots of the
benzylic isocyanate (0.01 mmol each) were dispensed into the
wells of the 96-well plates, pre-loaded with the stock solutions of
the amine coupling partners. The isocyanate/amine coupling
reactions were maintained at 35 ꢁC for 20 h, and then analyzed
by ultra-performance liquid chromatography-mass spectrom-
etry (UPLC-MS) to determine product identity by MS and an
approximate yield from the product peak area vs. total peak
areas obtained from UV absorption at 273 nm.
The desired benzylic ureas were obtained from 274 of the 288
reactions. Little congruence was evident between the high- and
low-yielding amines in the reactions with the three different
C–H substrates (Fig. 4C, center). To validate the structures and
yields of the products determined by UPLC-MS, eight
Subsequent efforts explored the scope of amine coupling part-
ners, emphasizing demonstration of the sequential C–H
isocyanation/amine coupling in a high-throughput platform
(Fig. 4A). A collection of 96 different amine coupling partners
was selected for testing in 96-well plates (Fig. 4B). The amines
were chosen to feature examples with both aliphatic and
aromatic substituents, including those with different substitu-
tion patterns and diverse functional groups, in order to assess
their compatibility with the isocyanation method. Overall, the
amine building blocks consisted of 43 aromatic (a1–d7, Fig. 4B)
and 53 aliphatic (d8–h12, Fig. 4B) amines, including primary/
secondary and cyclic/acyclic derivatives. The substrates incor-
porated a wide array of functional groups such as halogens,
nitro, (pinacolato)boronate, triuoromethyl, carboxylic esters
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Fig. 4 High-throughput synthesis of benzylic ureas. (A) Optimal reaction conditions for isocyanation/urea formation for synthesis of 288 ureas
from 3 C–H substrates and 96 amines. 1.3 and 0.01 mmol scale for isocyanation and urea formation respectively. (B) Amines on 96 well plates. (C)
Three representative C–H substrates (left), display of UPLC area percentages of urea products on three plates (center) and isolation result of
selected ureas (right). Reactions were reproduced in 0.2 mmol scale for isolation. Yields are presented as follows: (NMR yield of C–H iso-
cyanation X isolated yield of urea formation) overall isolated yield from scale-up reaction. The detection wavelength was 273 nm for UPLC
analysis.
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intermediate. The sequential process is amenable to high-
throughput experimentation, enabling rapid access to large
numbers of diverse ureas with drug-like physicochemical
properties using the benzylic C–H bond as the point of diver-
sication. The selectivity for benzylic over many other C(sp3)–H
bonds enables the vast array of (hetero)aromatic molecules to
be viewed and used as cross-coupling partners for synthesis of
bioactive compounds in drug discovery.
Data availability
Experimental details with screening results, characterization
data, NMR spectra, high throughput experimentation protocols,
and theoretical parameters of compounds (PDF) are provided in
the ESI.
Author contributions
S.-E. S., S. W. K., and S. S. S. conceived and planned the study. S.-
E. S. and L. E. N. carried out the synthesis and characterization. L.
E. N. performed the calculations of the physicochemical proper-
ties. All authors contributed to the analysis of the results and
manuscript preparation.
Fig. 5 Distribution of synthesized ureas on the plots versus molecular
properties. HBD, number of hydrogen bond donors; HBA, number of
hydrogen bond acceptors; MW, molecular weight; clog P, calculated
octanol–water partition coefficient; NRotB, number of rotatable
bonds; TPSA, topological polar surface area. The ranges associated
with the “beyond rule of five (bRo5)” designations for oral drugs are
defined in parentheses.
Conflicts of interest
There are no conicts to declare.
representative reactions were reproduced on 0.2 mmol scale.
The isolated yields of urea formation (Fig. 4C, right panel, blue-
colored font in parenthesis) measured from the scale-up
synthesis are almost always higher than those estimated from
high-throughput UPLC assay (Fig. S4–S6†). A minor exception is
the celestolide derivative A-a-1, which shows that the UPLC-
based product yield (48%, Fig. S4†) of urea formation is
nearly identical to that obtained from the scale-up experiment
(46%, Fig. 4C). Collectively, these results validate the high-
throughput results, and suggest they provide a lower bound
for yields that may be expected from larger scale reactions.
The relevance of this C–H isocyanation/amine-coupling
protocol for medicinal chemistry is reinforced by analysis of
the molecular properties of the urea products. Six physico-
chemical properties were computed for each product obtained
from the reactions in Fig. 4: number of hydrogen bond donors
(HBD), number of hydrogen bond acceptors (HBA), molecular
weight (MW), calculated octanol–water partition coefficient
(clog P), number of rotatable bonds (NRotB), and topological
polar surface area (TPSA) (Fig. 5). The computed parameters
show that the synthesized urea molecules51 closely align with
desirable properties dened by the “oral druggable space
beyond the rule of 5 (bRo5)” designations.52
Acknowledgements
We thank Dr Cyndi He (Merck & Co., Inc.) for valuable discus-
sions about cheminformatics during the course of this work.
This work was supported by funding from the NIH (R35
GM134929) and Merck & Co., Inc. (Kenilworth, NJ USA). Spec-
troscopic instrumentation was supported by a gi from Paul. J.
Bender, the NSF (CHE-1048642), and the NIH (1S10 OD020022-
1).
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