A General Copper-Catalyzed Synthesis of Ynamides from 1,2-Dichloroenamides

Article abstract of DOI:10.1021/acs.orglett.9b00971

Ynamides are accessed via copper-catalyzed coupling of Grignard or organozinc nucleophiles with chloroynamides, formed in situ from 1,2-dichloroenamides. The reaction exhibits a broad substrate scope, is readily scaled, and overcomes typical limitations in ynamide synthesis such as the use of ureas, carbamates, and bulky or aromatic amide derivatives. This modular approach contrasts with previous routes by installing both the N- and C-substituents of the ynamide as nucleophilic components.

Full text of DOI:10.1021/acs.orglett.9b00971

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A General Copper-Catalyzed Synthesis of Ynamides from 1,2-
Dichloroenamides
Steven J. Mansfield,† Russell C. Smith,‡ Jonathan R. J. Yong,† Olivia L. Garry,†
and Edward A. Anderson*,†
†Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, U.K.
‡Janssen PRD, 3210 Merryfield Row, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: Ynamides are accessed via copper-catalyzed
coupling of Grignard or organozinc nucleophiles with
chloroynamides, formed in situ from 1,2-dichloroenamides.
The reaction exhibits a broad substrate scope, is readily scaled,
and overcomes typical limitations in ynamide synthesis such as
the use of ureas, carbamates, and bulky or aromatic amide
derivatives. This modular approach contrasts with previous
routes by installing both the N- and C-substituents of the
ynamide as nucleophilic components.
namides (1, Figure 1) are valuable building blocks in
these substrates, preventing their wider exploitation in ynamide
chemistry.
Y
organic synthesis.1,2 As precursors to an array of reactive
We targeted an alternative route to ynamides in which the
disconnection point is shifted from C−N to C−C bond
formation. All previous examples of this tactic have employed
nucleophilic ynamide components (for example, in reactions of
metalated ynamides with C-centered electrophiles,13 or cross-
coupling of terminal ynamides,14 which can be complicated by
ynamide homodimerization). In contrast, the coupling of C-
centered nucleophiles with ynamide electrophiles is without
precedent, but is an appealing approach given the ready
availability of carbon-based organometallics.
In our previous work, chloroynamides 2 were identified as
intermediates en route to lithiated ynamides from 1,2-
dichloroenamides 3.13f We questioned whether these sub-
strates could instead serve as the electrophilic component in
C−C coupling, albeit only a single report exists on
chloroalkyne cross-coupling in general.15 Here we describe
the realization of this C-nucleophile coupling route to
ynamides, a method that displays broad substrate scope and
overcomes previous synthetic limitations such as high steric
hindrance on either the N- or C-component, and enables the
synthesis of acyclic urea-, carbamate-, and amide-ynamides.
To initiate studies, dichloroenamide 3a (Figure 2) was
prepared on 0.2 mol scale (66 g, 96%) from N-tosylaniline
using our reported conditions.13f Reaction of 3a with 1.2 equiv
of LiHMDS in THF enabled smooth conversion to
chloroynamide 2a. This could be isolated in good yield;16
however, for the purposes of ynamide synthesis it proved
equally convenient to perform the subsequent coupling in situ.
A number of copper salts (e.g., CuCl, CuBr·SMe2, CuI, CuCl2,
Figure 1. ‘Traditional’ and ‘umpolung’ copper-catalyzed ynamide
formation.
intermediates,3 they offer access to a wide variety of azacycles4
and are also of interest in medicinal chemistry.5 The prevailing
strategy for ynamide synthesis involves copper-catalyzed C−N
coupling of an amide nucleophile with an alkyne,6 haloalkyne,7
or dibromoalkene8 electrophile.9 Despite the utility of these
methods for substrates such as unhindered sulfonamides and
oxazolidinones, other classes of ynamide are far less accessible.
Acyclic amides, carbamates, and ureas are challenging coupling
partners10 as are N-aryl and sterically hindered amides, which
generally require prolonged heating to achieve even modest
conversions.7c,11 The use of alkynyliodonium triflates as
electrophilic coupling partners can overcome some of these
restrictions,10a,12 but a general solution remains elusive for
Received: March 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00971
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reaction solvent, and finally the catalyst loading could be
reduced to 1.25 mol % (2.5 mol % P(OMe)3) without
detriment. Under these optimized conditions, ynamide 2a was
isolated in 82−86% yield over five runs.20
These conditions were broadly applicable to couplings with
both Grignard and organozinc reagents (Figure 3a), with 38
organometallic coupling partners spanning a range of electron-
rich and electron-poor aromatics, and 1°/2°/3° alkyl groups,
being successfully converted to ynamides on reaction with 3a.
Amide, ester, nitrile, and nitro functionalities were tolerated
(1c, 1p−1s), as were potentially reactive halides (1h, 1n), and
hindered nucleophiles (1f−1i). A range of heterocyclic
Grignards also underwent efficient couplings (1t, 1w−1ab),
while the formation of ynamide 1al demonstrates an
interesting entry to alkynyl bicyclo[1.1.1]pentanes.21 Organo-
zinc partners proved useful where Grignard reagents were
unavailable or unstable, including several heteroaromatics (1u,
1v, and 1ac), albeit these substrates required extended reaction
times (12 h versus 10−30 min for Grignard coupling). For
many of these examples, the avoidance of prolonged heating
(as required for challenging ynamide C−N couplings) and the
use of readily available Grignard/organozinc reagents (which
obviates the need to preform haloalkene/alkyne coupling
partners) enhances the range of functionality that can be
introduced and affords opportunities to develop novel ynamide
reactivity. For instance, tolerance of nitro and fluoro
substituents in the formation of ynamide 1s enabled a concise
synthesis of aminoindole 8 (Scheme 1) via SNAr/cyclization.
Figure 2. Optimization of the conversion of dichloroenamide 3a to
ynamide 1a. Optimized conditions: PhMgBr (1.03 equiv), [CuCN·
2P(OMe)3] (1.25 mol %), TBME (0.34 M), 21 °C, 10 min, 82−86%.
a
CuCN) were screened as catalysts in the reaction with
PhMgBr (1.2 equiv),15,16 with all reactions reaching
completion in 10−15 min at 21 °C. However, alongside the
desired ynamide 1a, most also afforded (Z)-chloroenamide 4
as a significant side product (19−39%), along with small
amounts of 5−7.17 CuCN18 alone delivered 1a in high yield
and selectivity (79%, 1a:4 > 20:1). The inclusion of trimethyl
phosphite (10 mol %) minimized the formation of biphenyl
7,19 while decreasing the amount of PhMgBr to 1.03 equiv
suppressed the formation of 6. TBME proved a superior
Scheme 1. Synthesis of an Aminoindole from Ynamide 1s
Figure 3. Synthesis of sulfonamide ynamides. (a) Scope of organometallic coupling partners. (b) Scope of sulfonamide. All reactions were
conducted on 500 mg (1.46 mmol) scale using RMgX (1.03 equiv), [CuCN·2P(OMe)3] (1.25 mol %), TBME (0.34 M), 21 °C, 10 min−1 h,
unless otherwise stated. a Y = Cl·LiCl. b ArMgBr·LiBr was used. c ArZnCl·LiCl was used. d Z = TMP·LiCl. e TMEDA (1.3 equiv) was added. f Ar2Zn
was used.
B
DOI: 10.1021/acs.orglett.9b00971
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Figure 4. (a) Synthesis of carbonyl ynamides. (b) Reaction byproducts. (c) Reaction scope. a Ar2Zn prepared using a 2:1 ratio of ArMgBr (in
toluene or Et2O) and ZnCl2, Ar = Ph or 4-ClC6H4. b TMEDA (10 equiv) was added. The crystal molecular structure of 16 is displayed at 50%
probability;15 hydrogen atoms are omitted for clarity.
With the scope of the organometallic partner established, we
next tested a selection of N-sulfonyl dichloroenamides to
explore variation of the sulfonamide, and the steric/functional
group tolerance of the nitrogen substituent (Figure 3b).
Efficient reactions were observed irrespective of the nature of
either the sulfonyl motif (1am−1aq) or the nitrogen atom
substituent (1ar−1bb); particularly notable are ynamides 1aq,
1ay, 1az, and 1bb featuring bulky substituents on both the
nitrogen and alkyne (76−84%), and electron-deficient
sulfonamides 1ao and 1ap (78% and 76%).
Having developed a general approach to sulfonyl ynamides,
we decided to challenge the robustness of the transformation
by targeting acyclic carbonyl ynamides, which have otherwise
proven difficult to make. Carbamate dichloroenamide 9a,
which was readily prepared on multigram scale (42 mmol/12
g, 89%), was used as a test substrate (Figure 4a).
Chloroynamide formation (10) was achieved in 80−85%
yield; however, its coupling with PhMgBr led to significant
amounts of chloroenamides (Z)- and (E)-11 and (E)-
chloroester 12, in addition to the desired ynamide 13a (Figure
4b). These byproducts likely arise from competing addition of
the Grignard to the intermediate chloroynamide,16 but could
be suppressed through the use of diarylzinc reagents (prepared
by salt metathesis of the Grignard reagent with zinc(II)
chloride). The addition of TMEDA was also found to be
beneficial for the formation of urea-ynamides, and under these
reoptimized conditions, a range of carbamate and urea
dichloroenamides underwent smooth conversion to ynamides
13a−m (Figure 4c). These couplings were complete within 30
mina time scale that compares favorably with other
carbonyl-ynamide synthesis routeswith both diaryl and
dialkylzinc reagents proving effective.16
be minimized by conducting the elimination at room
temperature, enabling rapid coupling of chloroynamides to
give amide-ynamides 17b−e in good yields (Figure 4c).
In certain cases, the amide-ynamide products were prone to
hydration upon concentration, or during chromatography on
neutralized silica gel, giving δ-ketoamides (18a/f). This
remarkable β-hydration of the ynamide may be explained by
a 5-endo-dig cyclization22 to oxazolium ion 19 and subsequent
hydrolysis, and was particularly apparent for N-phenylamide
derivatives.23 In contrast, N-benzyl benzoyl ynamide 17e was
comparatively stable (68%), as were amide-ynamides featuring
bulky substituents (17b−d) where adoption of the con-
formation required for cyclization to the oxazolium ion may be
disfavored. It is surprising that these amide-ynamides are
somewhat fragile, given that equivalent carbamate- and urea-
ynamides are not; for example, urea 13l withstood heating in
ethanol during recrystallization. Although amide-ynamides
have been prepared sporadically in the past,10 it is clear that
the nature of the electron-withdrawing group and the second
nitrogen substituent are very important in modulating the
stability and reactivity of these compounds.
In summary, we have established a new strategy to access
ynamides from readily available dichloroenamides, in which
intermediate chloroynamides act as electrophilic components
in coupling with carbon-based nucleophiles. The reaction
shows broad scope, accommodating a wide range of Grignard
and organozinc reagents, and tolerating a diverse range of
functionality, electronic character, and steric bulk on both
coupling partners. This chemistry also offers a general route to
acyclic carbonyl-based ynamides and affords valuable insight
into their stability and reactivity. In overcoming many previous
limitations, this method provides a wealth of opportunities for
the development of new ynamide chemistry.
Acyclic amide substrates presented a significantly greater
challenge, with both reaction intermediates and products
displaying heightened reactivity compared to other derivatives.
For example, the conversion of dichloroenamide 14a to
chloroynamide 15 was accompanied by the unexpected
formation of 16 (Figure 4b), which likely arises from reaction
of 15 with the lithiated dichloroenamide.13 This side reaction,
which was not observed with any other substrate class, could
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00971.
C
DOI: 10.1021/acs.orglett.9b00971
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Full optimization details, experimental procedures,
1
copies of H and 13C NMR spectra and crystallographic
data (PDF)
Accession Codes
CCDC 1895057−1895071 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: edward.anderson@chem.ox.ac.uk.
ORCID
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Edward A. Anderson: 0000-0002-4149-0494
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.J.M. is grateful for support from an Oxford R. E. Jones
Scholarship, and the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1),
generously supported by AstraZeneca, Diamond Light Source,
Defence Science and Technology Laboratory, Evotec, Glax-
oSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB
and Vertex. R.C.S. thanks the SBM CDT for the industrial
partnership. E.A.A. thanks the EPSRC for additional support
(EP/M019195/1).
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DOI: 10.1021/acs.orglett.9b00971
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