A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology

Article abstract of DOI:10.1002/anie.201807393

The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high-yielding, mass-efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr₂, this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures.

Full text of DOI:10.1002/anie.201807393

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Accepted Article
Title: A Practical and General Amidation Method from Isocyanates
Enabled by Flow Technology
Authors: William J. Kerr, Jason Williams, Stuart Leach, and David
Lindsay
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807393
Angew. Chem. 10.1002/ange.201807393
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10.1002/anie.201807393
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COMMUNICATION
A Practical and General Amidation Method from Isocyanates
Enabled by Flow Technology
Jason D. Williams,[a,b] William J. Kerr,*[a] Stuart G. Leach,*[b] and David M. Lindsay[a]
Abstract: The addition of carbon nucleophiles to isocyanates
represents a conceptually flexible and efficient approach to the
preparation of amides. This general synthetic strategy has, however,
been relatively underutilized, due to narrow substrate tolerance, and
the requirement for less favourable reaction conditions. Herein, we
disclose a high-yielding, mass efficient, and scalable method with
appreciable functional group tolerance for the formation of amides by
reaction of Grignard reagents with isocyanates. Through the
application of flow chemistry, and the use of sub-stoichiometric
amounts of CuBr2, this process has been developed to encompass a
broad range of substrates, including reactants found to be
incompatible with previously published protocols.
The carboxamide is a ubiquitous motif within molecules
which find use in the pharmaceutical, agrochemical, and other
chemical industries.[1] Accordingly, over recent years, efforts
have focused on improved methods for amide formation which
avoid the use of stoichiometric activating agents. Whilst the
majority of this focus has been on catalysts for the condensation
of amines with carboxylic acids,[2] alternative methods have also
been widely explored.[3] Amongst these approaches,
isocyanates have recently received attention as a reactive and
mass-efficient synthon for the amide unit. Specifically, transition
metal-catalyzed cross-coupling reactions of isocyanates have
been developed, with both pre-formed organometallic species[4]
and following aryl C-H activation[5] (Figure 1a). These methods,
however, generally require forcing conditions and excess
reagents, and are only applicable to sp2-hybridized coupling
Figure 1. Synthesis of amides from isocyanates, by catalytic reactions, and
direct reactions with stoichiometric organometallic reagents.
delivered poor product yields, or been effective only in specific
cases,[13] until the more recent report of a protocol for the
reaction of isocyanates with Grignard reagents.[14] Despite this
notable advance, the latter method appears to be limited to
sterically hindered isocyanates. To our knowledge, no method is
currently capable of providing more widely effective amidation of
both sterically hindered and unhindered isocyanates, using sp2-
and sp3-coupling partners. Herein, we describe the development
of the first protocol in which such a general approach is fulfilled,
facilitated by the application of flow chemistry (Figure 1d).
Our initial studies were founded on an interest in
industrially-relevant amidation methods. This led to a detailed
exploration of the previously-reported[14] reaction of Grignard
reagents with isocyanates (Scheme 1). From these explorations
it was observed that a successful reaction requires a sterically
bulky isocyanate, otherwise formation of a deleterious acylurea
partners, due to β-hydride elimination issues.[6]
A nickel-
catalyzed reductive cross-electrophile coupling of isocyanates
with alkyl bromides has recently been reported,[7] alongside
similar methods involving phenol and benzylic alcohol
derivatives,[8] aryl iodides,[9] (Figure 1b), or the hydroamidation of
alkynes.[10] However, these approaches are generally limited to
hindered isocyanates, and require stoichiometric quantities of a
metal as the terminal reductant.
Non-catalyzed methods have capitalized on the prominent
electrophilicity of the isocyanate moiety[11] by reacting it directly
with a more nucleophilic organometallic reagent (Figure 1c).
This general approach has, however, received very little
attention, considering its theoretical simplicity. Organozinc
reagents have been shown to react ineffectively, in most cases
providing the carbamate product rather than the amide.[12]
Likewise, organolithium and Grignard reagents have generally
[a]
[b]
Prof. Dr W. J. Kerr, Dr D. M. Lindsay, Dr J. D. Williams
Department of Pure and Applied Chemistry
WestCHEM, University of Strathclyde
295 Cathedral Street, Glasgow, G1 1XL (UK)
E-mail: w.kerr@strath.ac.uk
Dr S. G. Leach, Dr J. D. Williams
GlaxoSmithKline
Medicines Research Centre
R1NCO
Entry
R2MgX
Yield (%)[a][b]
3aa, 32[c] 4aa, 23[c]
1
2
3
4
1a, R1 = Bn
1a, R1 = Bn
1b, R1 = tBu
1b, R1 = tBu
2a, R2= Ph(CH2)2, X=Cl
2b, R2=Mes, X=Br
2a, R2=Ph(CH2)2, X=Cl
2b, R2=Mes, X=Br
3ab, 16
3ba, 90
3bb, 85
4ab, 54
4ba, 0
4bb, 0
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY (UK)
E-mail: stuart.g.leach@gsk.com
Scheme 1. Initial studies, demonstrating poor reaction performance with
unhindered reaction partners. [a] Isolated yield of product shown. [b] Yield of 4
based on isocyanate starting material. [c] HPLC assay yield of product.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807393
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COMMUNICATION
by-product (4aa and 4ab) was observed in significant
quantities.[15] Attempts to prevent the formation of acylurea
through modulating temperature, addition regime, and reactant
stoichiometry delivered no practicable improvement.[16]
We then focused on a more detailed study of the low yielding
and inefficient coupling of unhindered reaction partners 1a and
2a. Surprisingly, the rate of Grignard reagent addition was found
to have a significant impact upon reaction performance (Figure
2). Slower Grignard addition considerably reduced the yield of
desired amide 3aa; from 69% using a fast addition by syringe, to
51% when a 10 second addition period was employed, and
appreciable lower yields of 3aa over longer Grignard addition
times.
Entry
Additive (equiv.)
Yield 3aa (%)[a]
Yield 4aa (%)[a]
1[b]
2[b]
3[b]
4[b]
5[b]
6[c]
7[c]
8[c]
9[c]
10[c]
None
TMSCl (0.5)
LiCl (1)
CuI (1)
CuBr2 (0.1)
None
TMSCl (0.5)
CuBr2 (0.1)
CuBr2 (0.01)
CuBr2 (0.005)
69
74
24
82
78
90
94
95
98
92
9
3
32
4
2
8
2
2
1
2
Scheme 2. Screening of additives in batch and flow, in order to suppress by-
product formation. [a] Yield determined by HPLC analysis, versus an internal
standard. [b] Reaction performed in batch. Conditions: 1a (1 mmol), 2a (1.1
mmol, 0.85 M in THF), additive, THF (4 mL), rt. [c] Reaction performed in
flow. Conditions: 1a (0.5 M THF solution with additive), 2a (0.5 M THF
solution), 5 mL/min pump rate, 10.6 s residence time, quenched into dilute
NH4Cl solution.
bromide to be preferable (entry 5). Examining the use of TMSCl
and CuBr2 in flow (entries 7-10) demonstrated that both
additives retained their effect, when compared with the additive-
free reaction (entry 6). Pleasingly, CuBr2 was found to deliver
further improvements upon lowering its loading to 0.01 eq. (entry
9), but upon further reduction to 0.005 eq. a drop in yield of 3aa
was observed (entry 10).[21] As illustrated in Scheme 3, the
optimal flow condition process (cf. entry 9) delivered a 96%
isolated yield of the desired amide, 3aa.
Figure 2. HPLC assay yields of desired amide 3aa and acylurea by-product
4aa versus total Grignard addition period. Reaction conditions: 1a (1 mmol),
2a (1.1 mmol, 0.85 M solution in THF), THF (4 mL), 0 °C, addition periods
were applied using a syringe pump.
This apparent requirement for rapid reagent addition then guided
us towards the application of continuous flow chemistry.[17]
Alongside addressing safety issues, this technology has been
recognized,
in
many
cases,
to
augment
reaction
chemoselectivity through enhanced mass and heat transfer. [18]
Indeed, when we applied a simple flow chemistry setup, a
distinct improvement was observed immediately, with an
increased yield of desired amide 3aa to 90%.[19]
Scheme 3. Diagram of flow chemistry set-up for the optimised reaction of
benzyl isocyanate 1a with phenethylmagnesium chloride 2a. [a] Isolated yield
of the desired amide 3aa on a 2.5 mmol scale.
Since no further improvement could be achieved by
parameter optimization, additives were screened in order to
suppress formation of acylurea 4aa in batch, and successful
conditions were then examined in flow (Scheme 2).
Trimethylsilyl chloride (entry 2) was found to be effective in
decreasing acylurea 4aa formation, presumably by transient
protection of the reactive metalated intermediate. Several known
Grignard de-aggregating agents[20] were also tested, such as
LiCl (entry 3), which, surprisingly, disfavored amide formation.
Copper salts were then applied to the reaction, with a successful
outcome observed when stoichiometric copper (I) iodide was
employed (entry 4). Further screening of copper sources
ultimately revealed a substoichiometric loading of copper (II)
With optimal conditions in hand, the substrate scope was
examined with respect to the isocyanate component (Scheme 4).
Gratifyingly, the developed protocol was found to give excellent
results with the vast majority of isocyanates examined, including
primary, secondary, and tertiary alkyl (3da, 3ea and 3ba),[22] aryl
(3ca), and substituted benzylic examples (3la and 3na; see also
3pa). This broad substrate scope demonstrates the applicability
of this methodology to any level of steric bulk around the
isocyanate. The reaction of most unhindered isocyanates were
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10.1002/anie.201807393
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ketone-containing isocyanate, amide 3ta was isolated in
moderate yield by reducing the reaction temperature to 0 °C.
Amide 3aa was also prepared on a 6.6 g scale in just twelve
minutes of continuous reaction, maintaining an excellent 95%
yield, and clearly demonstrating the inherent scalability of this
flow procedure.
The substrate scope was then explored with respect to the
Grignard reagent (Scheme 5). Simple aryl (3ab and 3ak), benzyl
(3ac), and vinyl (3ad) reagents performed very well, with either
the magnesium chloride or bromide Grignard reagent.
Additionally, a range of functional units and steric variation within
the Grignard reagent was tolerated successfully. For example,
an aryl chloride remained intact (3af), as did a THP-protected
phenol substrate (3ag). A bis(trimethylsilyl)-protected anilinic
Grignard reagent was also reacted successfully, and its
protecting groups removed in an acidic quench, to furnish the
primary aniline (3al) in excellent yield. Furthermore, a heteroaryl
Grignard reagent provided the thienyl amide (3ah) in good yield,
and the hindered 2,4,6-tri-iso-propyl derivative (3am) was also
prepared in a facile manner using this methodology. iso-
Propylmagnesium chloride and cyclopropylmagnesium bromide
gave good yields of amides 3aj and 3ae, respectively, but further
Scheme 4. Synthesis of secondary amides from a variety of isocyanates.
Reaction conditions: isocyanate 1 (1 mmol, 0.5 M in THF, with CuBr2, 0.01
mmol), Grignard reagent 2a (1 mmol, 0.5 M in THF), 5 mL/min pump rate, 10.6
s residence time, quenched into dilute NH4Cl solution. Isolated yields are given.
[a] No erosion of stereochemical purity was observed. [b] Reaction performed
at 0 °C. [c] Reaction performed on a 6.6 g scale. Cbz = carbobenzyloxy
previously unreported, whilst a bulky substrate (leading to 3ba)
performed comparably with the previously described method.[14]
Additionally, an ester group was tolerated (3fa) without any
requirement to lower the reaction temperature; moreover,
incorporation of an aryl nitrile unit was shown to be possible
(3ga). The successful reaction of a particularly electron-deficient
aryl isocyanate (3ia) was also considered noteworthy, as this
amide product would be challenging to prepare using standard
amide coupling procedures. Electronic variation on aryl rings
was well tolerated in general, with similar yields achieved for
unsubstituted (3ca), electron-rich (3sa), and electron-poor (3ka)
aryl isocyanates. Furthermore, the successful inclusion of a
chloride or bromide substituent (3ma and 3ha) provides a
handle for further functionalization in the product. Additionally,
the developed method was also applicable to other alkyl
isocyanates, providing good yields of products 3ja, 3oa, 3qa,
and 3ra, with maintenance of stereochemical integrity in the
latter example. Even with an electrophilic and readily enolizable
Scheme 5. Synthesis of secondary amides from
a variety of Grignard
reagents. Reaction conditions: isocyanate 1a (1 mmol, 0.5 M in THF, with
CuBr2, 0.01 mmol), Grignard reagent 2 (1 mmol, 0.5 M in THF), 5 mL/min
pump rate, 10.6 s residence time, quenched into dilute NH4Cl solution.
Isolated yields are given. [a] Reaction performed at 0.25 M input solution
concentrations. [b] 22% of regioisomeric by-product also isolated. [c] Product
synthesized using ArN(TMS)2 protected Grignard reagent, and deprotected in
quench using dilute HCl. THP = tetrahydropyranyl; and TMS = trimethylsilyl.
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COMMUNICATION
steric hindrance in an sp3 Grignard reagent was not tolerated, as
evidenced by the tert-butyl Grignard failing to furnish the desired
amide in an isolable quantity.[23]
Hesp, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2011, 133,
11430–11433; f) X. Geng, C. Wang, Org. Biomol. Chem. 2015, 13,
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[6]
[7]
For an overview of the problems associated with β–hydride elimination,
see: T.-Y. Luh, M.-K. Leung, K.-T. Wong, Chem. Rev. 2000, 100,
3187–3204.
In summary, a detailed assessment of the reaction of
isocyanates with Grignard reagents has led to the development
of a method in which, for the first time, a wide range of Grignard
reagents and isocyanates can be coupled effectively, using a
single, unified method. The use of flow chemistry imparts fast
mixing of both reagents, which is critical to the success of this
approach, but also confers upon this process an excellent
scalability and safety profile. Furthermore, this protocol avoids
the use of (stoichiometric) activating agents and provides an
efficient and productive transformation, demonstrating that
isocyanates are a valid surrogate synthon for the formation of
E. Serrano, R. Martin, Angew. Chem. Int. Ed. 2016, 55, 11207–11211;
Angew. Chem. 2016, 128, 11373–11377.
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[11] See also, amidations of isocyanates with carboxylic acids and
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amide bonds, particularly when
a non-nucleophilic amine
fragment is required. We anticipate that this development will
facilitate the practicable employment of isocyanates as part of a
genuine alternative synthetic strategy towards amide bond-
forming reactions.
[13] For selected examples of direct reactions of stoichiometric
organometallics with isocyanates, see: a) V. Pace, L. Castoldi, W.
Holzer, Chem. Commun. 2013, 49, 8383–8385; b) D. Seyferth, R. C.
Hui, Tetrahedron Lett. 1984, 25, 5251–5254; c) K. A. Parker, E. G.
Gibbons, Tetrahedron Lett. 1975, 16, 981–984; d) E. Chorell, P. Das, F.
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Meijere, Org. Lett. 2009, 11, 389–392.
Acknowledgements
[14] a) G. Schäfer, C. Matthey, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51,
9173–9175; Angew. Chem. 2012, 124, 9307-9310; See also, an
extension of this methodology to masked isocyanates: b) G. Schäfer, J.
W. Bode, Org. Lett. 2014, 16, 1526–1529.
The authors would like to thank the GlaxoSmithKline for financial
support to J.D.W. We would also like to thank Miss Sarah
Hunter, Mr. Andrew Payne, and Mr. Thomas Atherton for
support with engineering developments, reaction calorimetry,
and HRMS analysis, respectively.
[15] Formation of an analogous product was also observed in the iron-
catalyzed hydrophosphination of isocyanates: H. R. Sharpe, A. M. Geer,
W. Lewis, A. J. Blake, D. L. Kays, Angew. Chem. Int. Ed. 2017, 56,
4845-4848; Angew. Chem. 2017, 129, 4923-4926.
[16] For details, see section 3.1 in the supporting information.
[17] For selected applications of Grignard and other main group
organometallic reagents in flow, see: a) L. Huck, A. de la Hoz, A. Diaz-
Ortiz, J. Alcázar, Org. Lett. 2017, 19, 3747-3750; b) M. E. Kopach, K. P.
Cole, P. M. Pollock, M. D. Johnson, T. M. Braden, L. P. Webster, J.
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Keywords: amides • C-C coupling • synthetic methods •
Grignard reaction • flow chemistry
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[19] See section 2.3 in the supporting information for details.
[20] R. L.-Y. Bao, R. Zhao, L. Shi, Chem. Commun. 2015, 51, 6884–6900;
see also the additional detail within the supporting information.
[21] Investigation into the additive’s mechanism of action is currently
underway.
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[22] It has been shown that the tert-butyl group of amide 3ba can be
removed under Lewis acidic conditions, giving facile access to the
corresponding primary amide; see, A. K. Mahalingam, X. Wu, M.
Alterman, Tetrahedron Lett. 2006, 47, 3051–3053.
[23] The corresponding acylurea product (4an), equivalent to 4aa/4ab, was
isolated in 44% yield; see supporting information for further details.
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Entry for the Table of Contents (Please choose one layout)
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Jason D. Williams, William J. Kerr,*
Stuart G. Leach,* and David M. Lindsay
Page No. – Page No.
A Practical and General Amidation
Method from Isocyanates Enabled by
Flow Technology
Isocyanates represent a reactive and mass-efficient synthon for amide bond-
formation, yet their use with stoichiometric organometallic reagents has, in the past,
been hindered due to by-product formation in the majority of examples. We report
the development of a straightforward and widely applicable protocol, enabled by
continuous flow. For the first time, sp2- and sp3-carbon fragments can be
successfully reacted with a wide range of isocyanates using a single method.
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