Multiheterocyclic Motifs via Three-Component Reactions of Benzynes, Cyclic Amines, and Protic Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.7b03458

A broadly general, three-component reaction strategy for the construction of compounds containing multiple heterocycles is described. Thermal benzyne formation (by the hexadehydro-Diels-Alder (HDDA) reaction) in the presence of tertiary cyclic amines and a protic nucleophile (HNu) gives, via ring-opening of intermediate ammonium ion/Nu^- ion pairs, heterocyclic products. Many reactions are efficient even when the stoichiometric loading of the three reactants approaches unity. Use of HOSO₂CF₃ as the HNu gives ammonium triflate intermediates, which can then be ring opened by an even wider variety of nucleophiles.

Full text of DOI:10.1021/acs.orglett.7b03458

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Multiheterocyclic Motifs via Three-Component Reactions of
Benzynes, Cyclic Amines, and Protic Nucleophiles
Sean P. Ross and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, Minnesota 55455, United States
*
S Supporting Information
ABSTRACT: A broadly general, three-component reaction
strategy for the construction of compounds containing multiple
heterocycles is described. Thermal benzyne formation (by the
hexadehydro-Diels−Alder (HDDA) reaction) in the presence
of tertiary cyclic amines and a protic nucleophile (HNu) gives,
via ring-opening of intermediate ammonium ion/Nu− ion
pairs, heterocyclic products. Many reactions are efficient even
when the stoichiometric loading of the three reactants
approaches unity. Use of HOSO CF as the HNu gives
2
3
ammonium triflate intermediates, which can then be ring opened by an even wider variety of nucleophiles.
6
7
he rapid construction of complex products from simple
starting materials has driven the development of numerous
sulfide addition or alkaloidal natural products. We now report
that a diverse array of multiheterocyclic products can be
efficiently assembled in a single, thermally driven operation.
Substrate 6 (Scheme 1b) cyclizes in a rate-limiting event to the
benzyne 7 that, in the presence of a cyclic amine 8 and proton
source 9, gives the ion pair 10, which ring opens to the three-
component product P#. There is considerable breadth in each of
the three classes of reactants that readily participate: the benzyne
precursors (6a−f, Figure 1, panel i), the cyclic tertiary amines
(8a−j, Figure 1, panel ii, nonbicyclic; and 8k−n, Figure 3, panel i,
bicyclic), and the protic nucleophiles (9a−m, H−Nu, Figure 1,
panel iii). We note that in the absence of a tertiary amine most of
the protic nucleophiles 9 are capable of engaging HDDA
benzynes, indicating that the reaction rate of addition of the
cyclic amine 8 is considerably faster than that of 9.
T
synthetic strategies. These include a wide variety of multi-
component reactions that allow for the modular generation of
1
structural complexity and diversity. One example is initiated by
the nucleophilic addition of tertiary amines to benzyne (1,
2
Scheme 1a). This is thought to proceed by initial 1,3-zwitterion
Scheme 1. Three-Component Reactions of Benzynes,
Tertiary Cyclic Amines, and Protic Nucleophiles (H-Nu)
We did not undertake an exhaustive survey of every possible
combination, but rather chose to explore a representative subset
to display the versatility of this strategy. The tri- or tetrayne
precursors 6 cyclize to produce the benzynes 7 with convenient
half-lives of reaction of a few hours at temperatures ranging from
8
0−130 °C. One limitation is that triynes containing an ynoate
or an ynone subunit gave variable results; presumably because
these electron-deficient alkynes reacted prematurely with some
8
of the more nucleophilic tertiary amines. This could be
mitigated by using ynoates and ynamides containing a bulky
TBS group on the terminus of the conjugated alkyne (cf. 6b and
6f).
3
formation (cf. 3), which then engages either a carbonyl
2
c−e
2a,b,f
compound
or a proton source (cf. 4).
when strained (cf. aziridines and azetidines 2), lead to adducts 5
in the presence of acetonitrile or carboxylic acids in a process
involving nucleophilic opening of the ion pair 4.
The thermal cycloisomerization of tethered tri- and tetraynes
leads to benzynes under neutral conditions in a process we have
termed the hexadehydro-Diels−Alder (HDDA) reaction. These
can then participate in myriad novel trapping processes,
including three-component reactions (TCRs) initiated by cyclic
Cyclic amines,
We describe here three categories of TCR. These differ in the
use of: monocyclic tertiary amines (including N-arylpyrrolidines
and -piperidines, Figure 2), bicyclic amines with a bridgehead−
2a
2f
4
nitrogen atom (Figure 3), and arylammonium triflates (10, Nu
−
=
TfO ).
5
Received: November 7, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Three classes of reactants (i−iii) used to prepare the TCR
products P# in Figures 2−4.
Figure 2. Three-component reactions of HDDA-generated benzynes
with monocyclic tertiary amines and protic nucleophiles. (a) The three
letter code beside the yield data for each entry identifies the specific
example of 6, 8, and 9, respectively (Figure 1) used to prepare each P#
compound. (b) TCRs were performed using 1.2−3 equiv of the cyclic
amine 7 and 1.2−2 equiv of the protic nucleophile 9 (see the SI for
details) and a starting concentration of 6 of 0.05 M.
We have elected to identify the structures of each product of a
TCR in this manuscript by a preceding “P” followed by a unique
number, in sequence throughout. Thus, P1−P17 are the
products in Figure 2. The three-letter code in parentheses
indicates the first (polyyne 6), second (amine 8), and third
(
nucleophile 9) components used to prepare each product. Each
benzyne intermediate in this study was unsymmetrical; as such,
each could react in two different ways with the nucleophilic
amine. The major constitutional isomer of the product is shown
a single regioisomer (P13−P17), a reflection of both
10
predistortion of the benzyne ring and the added steric
congestion adjacent to one of the two benzyne carbons. Various
nitrogen-containing heterocycles are compatible with the
process, including as a preexisting substituent on the cyclic
amine (cf. P12, P14, and P17) or as the protic nucleophile (cf.
P7, P8, P12, and P17).
(see the Supporting Information (SI) for characterization of both
isomers); the regioselectivity of the reaction is given in
parentheses as the ratio of major to minor products. For
example, P5 (acb, 96%, 3:1) arose from the TCR of 6a, 8c, and
9
b to give a 3:1 ratio of isomers in 96% yield (of chromato-
We next turned our attention to the use of the bicyclic amines
8k−n (Figure 3), each containing a bridgehead nitrogen atom.
graphically purified material).
11
These TCRs of N-alkyl cyclic amines are limited to strained
ring compounds since dealkylation of the exocyclic alkyl group is
a seriously competitive process (see the SI). In contrast, N-
arylated piperidines, pyrrolidines, and morpholine (8a−e)
undergo efficient ring-opening to give the three-component
adducts P1−P9, P15, and P16. Electron-deficient aniline
derivatives were not as effective in capturing the benzyne (e.g.,
cf. yields of P6 vs P5). N-Alkylazetidines and -aziridines (8g−j)
are competent TCR partners. Products P7−P9, P12, and P17
demonstrate successful trapping by a variety of nitrogenous
nucleophiles; all other products in Figure 2 arose from the use of
oxygen-based nucleophiles.
These gave rise to aryl piperazines P18−P28 [each from
12
DABCO (8k)] and aryl piperidines P29−P31, motifs often
13
viewed as privileged structures in drug discovery efforts. As can
easily be discerned from the structures in Figure 3, a considerably
diverse array of multiheterocyclic products can be efficiently
generated by this strategy. The stoichiometric ratio among the
three substrates 6:8:9 (ca. 1: ≤ 1.5: ≤ 1.5) is particularly
noteworthy, suggesting that any or all of the three participants
could be of considerable structural complexity. Note that (i)
many different classes of nitrogen-containing heterocycles are
compatible with the process; (ii) chloride can be introduced by
performing the reaction in chloroform solution and in the
The benzynes from 6a and 6b often proceed with low levels of
regioselectivity. In contrast the benzynes from 6c−6f give only
absence of any additional proton source (P25; we have observed
7
,9
−
a similar chloride ion transfer from, presumably, Cl C in a
3
B
DOI: 10.1021/acs.orglett.7b03458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Use of ammonium triflate intermediates allows for
incorporation of an even broader range of nucleophiles. (a) The three
letter code beside the yield data for each entry identifies the specific
example of 6, 8, and 9, respectively (Figure 1), used to prepare each P#
compound. (b) TCRs were performed using 2−3 equiv of the cyclic
amine 7 and 1.1−2 equiv of triflic acid in acetonitrile (MeCN) (see the
SI for details) and a starting concentration of 6 of 0.05 M. The resulting
triflate salts were then subjected to 3−10 equiv of the nucleophiles 9n−s
in the specified solvents (see the SI for details).
Figure 3. Three-component reactions of HDDA-generated benzynes
with bicyclic amines and protic nucleophiles. (a) See notes a and b in
Figure 2. (b) Ratio of cis/trans isomers.
3
recently reported mechanistic study ); and (iii) use of the
quinuclidinol derivatives 8l−m allows for facile introduction of
additional heteroatoms into the products (cf. P29−P31).
All of the single-step TCRs described in Figures 2 and 3 meet
the following criteria: (i) neither the amine or the protic
nucleophile should react with the HDDA precursor faster than its
rate of cyclization; (ii) the tertiary amine should add to the
benzyne faster than does the protic nucleophile; (iii) the protic
nucleophile (H-Nu) should be acidic enough to protonate the
set: (i) sodium benzenesulfinate (9n) produced a mixture of
sulfone P32 and sulfenic ester P33; (ii) sodium amide salts 9p
and 9t gave rise to the triazole P35 and indole P40, respectively;
(iii) a heterocyclic thiol (9q) led to the sulfide P36; (iv) dimethyl
sodiomalonate (9o) gave esters P34 and P38; (v) morpholine
(9r) produced the tertiary amine P37; and (vi) sodium azide
(9s) gave the azides P39. Through this protocol the scope of
compatible nucleophiles is significantly broadened.
Nearly all of the types of products produced through the TCRs
described here can, in principle, be further diversified to give a
wide range of heterocycle-rich small molecules. We show
examples in Figure 5. The newly introduced heterocycles (in
green) include: oxazolidinone (P41), benzopyrazole (P42),
pyrrolopiperidine (P43), and triazoles (P44−P46). Other
similar transformations are easily imagined.
14
intermediate 1,3-zwitterion; and (iv) the conjugate base of H-
Nu should be sufficiently nucleophilic to ring open the aryl
ammonium intermediate (cf. 10, Scheme 1).
We hypothesized that several of these limitations would be
circumvented through a two-step process involving the
formation and subsequent nucleophilic ring-opening of stoichio-
15
metric ammonium triflates 10-OTf (Figure 4). Indeed, if a
benzyne 7 is produced from 6 in a solution containing both free
tertiary amine and its ammonium triflate, the triflate salts 10-OTf
16
are produced in stoichiometric fashion. For the examples
shown in Figure 4, N-phenylpiperidine, N-phenylmorpholine, or
DABCO was the amine component. The triflate was then
exposed to a nucleophile to effect a two-step, three-component
coupling. The examples in Figure 4 use one of 9n−t as the
nucleophile, but these by no means constitute a comprehensive
In conclusion, we have developed the three-component
reaction of HDDA-generated benzynes, cyclic tertiary amines,
and protic nucleophiles. Many amines productively engage the
benzyne, including N-aryl and N-alkyl cyclic amines and bicyclic
amines containing a bridgehead nitrogen atom (8a−n). Many
protic nucleophiles are effective (9a−s). The use of ammonium
C
DOI: 10.1021/acs.orglett.7b03458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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triflate intermediates increases the scope of compatible
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the rapid construction of multiheterocyclic compounds.
(
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ASSOCIATED CONTENT
Supporting Information
Biol. 2010, 14, 347−361.
■
(
14) We carried out the following NMR experiment to verify that the
*
S
newly incorporated, aromatic hydrogen atom in the benzenoid product
originated from the protic nucleophile. Substrate 6a, amine 8a, and
CH COOD or CD COOD were heated in benzene-d . In each case,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03458.
3
3
6
product P1 was primarily (the solution at time zero showed evidence of
Experimental procedures, characterization data, and
copies of all H and C NMR spectra for all isolated
compounds (PDF)
1
13
a small amount of protium from H O in the reactants and < 100%
2
labeling of the acetic acid) deuterated by integration of the (residual)
aromatic proton resonance and reinforced by ESI-MS analysis.
(
15) In all cases the triflate salts were freed of solvent (CH CN) prior
3
AUTHOR INFORMATION
Corresponding Author
to being used for the subsequent nucleophilic ring opening. To
demonstrate additional parameters, we precipitated with ether and
isolated by filtration the ammonium triflate that leads to P40. This solid
material was spectroscopically characterized, although as an admixture
with remaining DABCOH ·TfO . This material was stored for over 2
years with no appreciable change in integrity.
■
*
E-mail: hoye@umn.edu.
ORCID
+
−
Thomas R. Hoye: 0000-0001-9318-1477
Notes
(16) (a) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.;
Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199−5202.
(b) Bhojgude, S. S.; Kaicharla, T.; Biju, A. T. Org. Lett. 2013, 15,
The authors declare no competing financial interest.
5
452−5455. (c) Hirsch, M.; Dhara, S.; Diesendruck, C. E. Org. Lett.
ACKNOWLEDGMENTS
This work was supported by the U.S. Department of Health and
Human Services, National Institute of General Medical Sciences
2016, 18, 980−983.
■
(
GM-65597). NMR spectral data were obtained with an
instrument procured with a grant from the National Institutes
of Health Shared Instrumentation Grant program
(
S10OD011952). We thank Mr. Juntian Zhang for performing
the representative example of a 1 mmol scale reaction (see the
SI).
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DOI: 10.1021/acs.orglett.7b03458
Org. Lett. XXXX, XXX, XXX−XXX