Synthesis of bicyclic guanidines via cascade hydroamination/michael additions of mono- n -acryloylpropargylguanidines

Article abstract of DOI:10.1021/ol502691w

A cascade silver(I)-catalyzed hydroamination/Michael addition sequence has been developed to deliver highly substituted bicyclic guanidines. This transformation gives rise to geometrically and constitutionally stable ene-guanidines and generates a remote stereocenter with moderate to high diastereoselectivity.

Full text of DOI:10.1021/ol502691w

Letter
pubs.acs.org/OrgLett
Synthesis of Bicyclic Guanidines via Cascade Hydroamination/
Michael Additions of Mono‑N‑acryloylpropargylguanidines
Ki-Hyeok Kwon,† Catherine M. Serrano,† Michael Koch,‡ Louis R. Barrows,‡ and Ryan E. Looper*,†
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
‡Department of Pharmacy/Toxicology, University of Utah, 30 South 2000 East, Salt Lake City, Utah 84112 United States
S
* Supporting Information
ABSTRACT: A cascade silver(I)-catalyzed hydroamination/Michael
addition sequence has been developed to deliver highly substituted
bicyclic guanidines. This transformation gives rise to geometrically and
constitutionally stable ene−guanidines and generates a remote
stereocenter with moderate to high diastereoselectivity.
Scheme 1. Synthetic Strategy for the Bicyclic Guanidines
olycyclic guanidinium ion natural products exhibit a broad
spectrum of biological activity and embed an important
P
structural unit that is critical for medicinal chemistry and for
broader discovery-based applications.1 Unnatural polycyclic
guanidines have also been employed as competent organo-
catalysts with unique coordination arrangements and an array of
donor/acceptors.2,3 Given their broad utility, a variety of
synthetic methods have been developed to access this class of
compounds. Some of these methods include the cyclization of
propargylguanidines,4 intermolecular diamination of alkenes,5
reaction of unsaturated molecules with aziridines and diazirenes,6
intramolecular alkylation of guanidines,7 and radical cascade
cyclizations,8 among others.9 Very recently, titanium amides have
been shown to catalyze the synthesis of cyclic guanidines from
diamines and carbodiimides in a single step.10 Unfortunately,
most of these synthetic routes require multistep synthesis or
preparation of highly functionalized precursors. The develop-
ment of advanced, efficient, and facile methods to access these
compounds thus remains an important goal for synthetic
chemists.11 Herein, we report a one-step Ag(I)-catalyzed
hydroamination/Michael addition sequence of mono-N-acryl-
oylpropargylguanidines yielding bicyclic guanidines with com-
plete regiocontrol and modest to high levels of 1,5-asymmetric
induction.
The synthesis of unsymmetrical guanidines has been
intensively investigated, and a variety of guanylating agents are
available.12 We recently reported the chlorotrimethylsilane
activation of acylcyanamides as an efficient method for the
synthesis of mono-N-acylguanidines via a reactive N-silylcarbo-
diimide intermediate.14
This discovery prompted us to consider new types of
guanylating agents, capable of engaging cascade reactivity
which could lead to the formation of bicyclic guanidines. We
became interested in the unsaturated N-cyanoacylamide 1 as a
guanylating agent and precursor for bicyclic guanidines (Scheme
1). Upon reaction with TMSCl, N-cyanoacylamide 1 should
generate an N-silylcarbodiimide intermediate capable of reaction
with a propargylamine 2. Acryloylguanidines (e.g., 3) themselves
do not undergo intramolecular cyclization due to internal
hydrogen bonding by the NH2 group to the carbonyl, locking it
in an unproductive s-cis conformer. We envisioned that initial 5-
exo selective cyclization of the guanidine on a tethered alkyne
would generate an intermediate that can undergo rapid s-cis → s-
trans isomerization by the introduction of significant pseudo-A1,3
strain. This would then allow the formation of the 6-membered
ring via Michael addition with the unsubstituted guanidine
nitrogen (N2) (Scheme 1). If successful, this would provide
access to highly substituted 5,6-membered bicyclic guanidines.
To execute this strategy, we first examined the direct activation
of the N-cyanoacrylamides 1a−h and their reaction with
propargylamine 2a (Table 1). The reaction of both 1a and 1b
with 2a yielded products 3a/b in moderate yields (entries 1 and
2). The reaction of more electron-deficient cinnamoyl derivatives
(1c−e) with 2a gave better yields of propargylguanidines 3c−e
(entries 3−5). Conversely, the more electron-rich N-cyanoacry-
lamide (1f) gave its corresponding propargylguanidine in
attenuated yield (entry 6). The reactivity of these intermediate
N-silylcarbodiimides appears to be acutely sensitive to the
electronic nature of the N-cyanoacrylamides. For example, the
more electron-rich substrates 1g/h, which are β-disubstituted,
fail to react with 2a (entries 7 and 8).
Having synthesized the required substrates, we next
investigated the cascade cyclization−Michael addition sequence.
Indeed, Ag(I) initiated a highly selective 5-exo cyclization
Received: September 11, 2014
Published: November 13, 2014
© 2014 American Chemical Society
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guanidine, allowing us to intuitively assign the syn-diastereomer
as the thermodynamically favored product. Prior to the Michael
addition, torsional strain between R3−R4−R5 might preferen-
tially position the Michael acceptor above or below the plane of
the cyclic guanidine depending on the relative torsion this
interaction imparted to the N3−carbonyl bond. Examples of
Ag(I)-catalyzed Michael additions of amines are rare,15 and we
were doubtful that catalysis of this step would significantly impact
the reaction outcome. Probing these torsional effects on the
reaction outcome guided our substrate analysis.
Table 1. Survey of Guanylation Activity with N-
Cyanoacrylamides
a
b
entry
cyanamide (1)
R1 = H, R2 = Ph (1a)
products (3) yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
63
60
83
78
73
36
0
We first examined substrates where R4 = aryl, anticipated to
behave as a large substituent (Figure 1). All substrates in this
R1 = H, R2 = 2-naphthyl (1b)
R1 = H, R2 = C4H6-o-Br (1c)
R1 = H, R2 = C4H6-m-CF3 (1d)
R1 = H, R2 = C4H6-p-Br (1e)
R1 = H, R2 = 1,3-benzodioxolyl (1f)
R1 = Me, R2 = Me (1g)
3g
3h
R1 = Me, R2 = Ph (1h)
0
a
Reaction conditions: cyanamide (1.0 mmol), amine (1.0 mmol),
b
TMSCl (1.2 equiv), NEt3 (1.5 equiv), CH2Cl2 (10 mL), 8 h. Isolated
yield. TMSCl = chlorotrimethylsilane, NEt3 = triethylamine.
guanidine as previously reported.5a−c Accordingly, treatment of
3a in the presence of AgNO3 (10 mol %) in acetonitrile at room
temperature provided 4a in good chemical yield as a mixture of
two diastereoisomers that were readily separable by chromatog-
raphy (78% yield, dr = 2:1) (Scheme 2). It is important to note
Scheme 2. Synthesis of Bicyclic Guanidines from
Propargylguanidines and Confirmation of Their
Stereochemistry by X-ray Crystallography
Figure 1. Substrate scope for the cyclization/Michael addition catalyzed
by AgNO3 where R4 = aryl. Reaction conditions: substrate (0.3 mmol),
AgNO3 (10 mol %), MeCN (0.1 M), 8 h. The diasteromeric ratios were
determined by 1H NMR analysis of the crude mixture.
that the initial hydroamination proceeds with excellent
regiochemical control via attack by the imino-nitrogen (N3), as
drawn. After the stereochemistry of syn-4a and anti-4a was
confirmed by X-ray crystallography, it became straightforward to
identify the relative configurations of these products by the larger
series were tolerated, giving the products in good chemical yield
and similar diastereoselectivities. Examples 4b−d demonstrate
that a variety of electron-withdrawing and -donating groups on
the acryloylguanidine are tolerated to give the products in good
chemical yield and similar diastereoselectivities. Substitution of
the alkyne substituent (R5) to a smaller alkyl group also had no
effect on diastereoselectivity (4e). Introduction of a larger o-
substituted aryl group (4f) or a larger group at N1 was also
inconsequential (4g−i). Unexpectedly, we found that the 2-
naphthyl-substituted acryloylguanidines cyclized with enhanced
diastereoselectivity 10:1 dr for 4j and 5:1 dr for 4k. While
independently the interaction R3−R4−R5 is critical for selectivity,
the interactions do appear to be additive. For example, a large
substituent at N1 and C3 (e.g., m-(trifluoromethyl)phenyl)
improves the selectivity to 10:1 dr (4l). Inclusion of the 2-
3
diaxial J coupling between H4 and the neighboring methylene
group in the anti-diastereomer. As expected from an anti-
aminometalation pathway, the products are formed as single
geometric isomers the C−C double bond. The fact that this
transformation proceeded with modest diastereoselectivity was
surprising, given that the two stereocenters are five atoms apart
and separated by an almost planar 5,6-fused heterocyclic system.
When the crystal structures of syn/anti-4a were evaluated, it was
noted that the anti-diastereomer had considerable torsional
strain about the C2−C3 bond. The alkene is bent significantly out
of the plane with N3, deconjugating the alkene from the
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naphthyl group enhances the diastereoselectivity of the product
4m to >20:1 by 1H NMR.
We next examined substrates where R4 = alkyl or α-branched,
anticipated to behave as a small group by virtue of their ability to
orient a methyne hydrogen toward the alkene (Figure 2). Quite
Figure 3. Substrate scope for the cyclization/Michael addition catalyzed
by AgNO3 where R4 = H. Reaction conditions: substrate (0.3 mmol),
AgNO3 (10 mol %), MeCN (0.1 M), 8 h. The diastereomeric ratios were
determined by 1H NMR analysis of the crude mixture. b Performed on a
2.5 mmol scale.
Scheme 3. Transformation of the Resultant Bicyclic
Guanidines
Figure 2. Substrate scope for the cyclization/Michael addition catalyzed
by AgNO3 where R4 = alkyl. Reaction conditions: substrate (0.3 mmol),
AgNO3 (10 mol %), MeCN (0.1 M), 8 h. The diastereomeric ratios were
determined by 1H NMR analysis of the crude mixture.
to our surprise, all of these substrates cyclized with higher
diastereoselectivity but favored the anti-diastereomer. The
substrates where R4 = benzyl or isopropyl gave anti-5a and
anti-5b in good diastereoselectivity (10:1 dr or >20:1 dr,
respectively). Deletion of a substituent on the alkyne did lower
the diastereoselectivity to 4:1 dr as seen with 5c. Other
substituent interchanges still delivered the products (5d−i)
with good levels of anti-diastereoselectivity ranging from 5:1 to
>20:1 dr.
In the context of delivering a small collection of this new
scaffold for initial biological evaluation, we also examined this
cascade reaction on substrates lacking a substituent at R4 (Figure
3). A variety of substituents on the N1 guanidine nitrogen were
well tolerated, generating the corresponding bicyclic products in
good chemical yield (6a−i). More electron-rich alkyne
substituents were also tolerated (6e). All of the Michael
acceptors examined were also tolerated (6f−i). Notably, this
synthetic procedure is scalable and practical providing 6d in 67%
yield when performed on a 2.5 mmol scale.
These architectures comprise other functional groups that can
be engaged. For example, reduction of the ene−guanidine in 6d
cleanly provides the saturated tetrahydroimidazolpyrimidone 7
(Scheme 3a). Attempts to isomerize the alkene and generate the
dihydroimidazolpyrimidone under acidic conditions were
unsuccessful. Exposure of 6d to 1:1 CH2Cl2:TFA returned the
starting material with the alkene both constitutionally and
geometrically intact. We did, however, observe that the alkene
could be isomerized under hydrogenolysis conditions. In the
presence of a nucleophilic solvent, the ring-opened methyl ester
8 can be obtained, representing an interesting entry to N-
imidazolyl-β-amino ester (Scheme 3b). Interestingly, attempts to
isomerize the alkene in anti-5f with HCl/Et2O/MeOH did not
affect the alkene (Scheme 3c). Instead, epimerization occurred at
3
C4, as evidenced by the smaller diaxial J coupling to H4,
suggesting that the Michael addition is reversible under acidic
conditions and that the syn-diastereomer is indeed thermody-
namically preferred. It should be noted that resubjection of the
isolated diastereomers or mixtures thereof to the original Ag-
catalyzed reaction conditions does not change the product ratio,
suggesting that the initial product ratio is kinetic.
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intriguing scaffolds identified several members to be inhibitory
toward the growth of an attenuated strain of Mycobacterium
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In summary, we have developed a method for the synthesis of
highly substituted bicyclic guanidines in good to excellent yields
from readily accessible propargylguanidines. This cascade
hydroamination−Michael addition sequence gives rise to
products as a single regioisomer and with a constitutionally
and geometrically stable ene−guanidine functional group.
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atoms removed and spanned by an almost planar heterocyclic
core. These interesting scaffolds have already garnered our
interest as antitubercular agents. The modularity of this approach
should expedite follow-up investigations to identify candidates
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
R.E.L. thanks the NIH, General Medical Sciences (R01
GM090082, P41 GM08915), Curza, Amgen, and Eli Lilly for
financial support. L.R.B. thanks the ICBG (5UO1TW006671)
for funding.. We are grateful to Prof. Matt S. Sigman and Prof.
Jon D. Rainier for insightful discussions.
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