Regioselective rhodium(II)-catalyzed hydroaminations of propargylguanidines

Article abstract of DOI:10.1002/anie.201006087

Different than others: Dimeric rhodium(II) carboxylates uniquely catalyze the 6-endo-dig selective hydroamination of propargylguanidines while tranditional π-Lewis acids are typically 5-exo-dig selective (see scheme, oct=octanoate). Furthermore, this repr

Full text of DOI:10.1002/anie.201006087

Communications
DOI: 10.1002/anie.201006087
Rhodium Catalysis
Regioselective Rhodium(II)-Catalyzed Hydroaminations of
Propargylguanidines**
Morgan J. Gainer, Nitasha R. Bennett, Yu Takahashi, and Ryan E. Looper*
Cyclic and polycyclic guanidinium ion natural products have
been shown to modulate a variety of important biological
processes and their activities are often reliant on the unique
hydrogen bond donor–acceptor topologies that these sub-
structures display.[1] While most synthetic methods to prepare
guanidines rely on the addition of an amine (guanylation) of
an activated thiourea or urea,[2] alternative methodologies
the power of this approach in total synthesis. Achieving
selectivity in these hydroaminations, particularly 5-exo-dig vs.
6-endo-dig, would present a valuable tool for the synthesis of
complex guanidine-containing natural products. Here, we
describe the discovery of an unusual reactivity of dirhodiu-
m(II) carboxylates as highly 6-endo-dig selective hydroami-
nation catalysts in the cyclization of propargylguanidines,
while AgI is typically 5-exo-dig selective.
À
that generates peripheral C N bonds from an intact guani-
dine nucleus have proven powerful for the preparation of
We first examined the ability of traditional p-Lewis acids
to catalyze the hydroamination of 1a (Table 1). Initial
polycyclic guanidine natural products.[3a–e]
Our interest in the biological activity of guanidine natural
products has prompted us to develop a synthetic platform that
is capable of delivering cyclic guanidines having multiple ring
sizes, substitution patterns, and oxidation states in short order.
To this end we have been interested in the addition of
Table 1: Catalyst screen for propargylguanidine hydroamination.
À
À
guanidine N H bonds across C C p systems and recently
reported a LaIII-catalyzed tandem addition–hydroamination
reaction of propargylcyanamides which required forcing
conditions, and resulted in exclusive 5-exo-dig cyclization.[4]
This led us to study the hydroamination of preformed di-Boc
protected propargylguanidines of the type 1, in hopes of
finding a 6-endo-dig selective process. Traditionally, metal-
catalyzed cyclizations on alkynes favor a 5-exo-dig pathway.
This can be seen in AuI- and AuIII-catalyzed cyclization of
propargylcarbamates, propargylureas, and propargyla-
mides,[5,6] as well as the TiIV–amide hydroamination reactions
of homopropargylamines.[7,8] Examples of cyclization of
heteroatom nucleophiles onto alkynes leading to 6-endo-dig
cyclization, although as synthetically significant as the 5-exo-
dig products, are nevertheless much less common and usually
observed with substrates in which the tether is largely sp2
hybridized.[9,10]
Entry
Catalyst[a]
Solvent
t [h]
Selectivity[b]
2:3:4
Yield
[%][c]
.
1
2
3
4
(CuOTf)2 Ph
Pd(OAc)2
AgOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
48
12
3
5
2
168
60
60
60
16
1:4.6:1
1:4:0
1:16:0
1:>20:0
1:>20:0
4:1:0
3:1:0
6:1:0
13:1:0
>20:1:0
31
55
52
55
90
21
n.d.
n.d.
47
AgOAc
AgOAc
5[d]
6
NaAuCl4
AuCl3
[Rh2(tfa)4]
[Rh2(OAc)4]
[Rh2(oct)4]
7
8
9
10
81
[a] All catalysts were screened at 10 mol% loading. OTf=trifluorome-
thanesulfonate, OAc=acetate, tfa=trifluoroacetate, oct=octanoate,
AcOH=acetic acid. [b] Product selectivities determined by 1H NMR
spectroscopy; >20:1 indicates a single regioisomer. [c] Yields of isolated
product. [d] 3 equiv of AcOH were used as additive.
During the preparation of this manuscript, Gin and co-
workers described the AuCl3-catalyzed hydroamination of
alkynes with 2-aminopyrimidines in the synthesis of crambe-
dine.[11] Their gold-catalyzed 6-exo-dig cyclization highlights
experiments highlighted that there were multiple reaction
pathways available (Table 1, entry 1). Cyclization of 1a in the
presence of CuI salts reliably gave a mixture of 6-endo-dig and
5-exo-dig products (2a and 3a, respectively) that are easily
[*] M. J. Gainer, N. R. Bennett, Y. Takahashi, Prof. Dr. R. E. Looper
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
3
4
E-mail: r.looper@utah.edu
identified by the magnitude of either J or J coupling. From
nOe experiments it was also confirmed that the 5-exo product
3a carried the Z-alkene configuration. The unanticipated
product was the yne-guanidine 4, which may arise from a
[1,3]-prototropic shift followed by isomerization as detailed
by Gevorgyan et al. for propargyl acetates.[12]
[**] We thank the NIH, General Medical Sciences (R01 GM090082), and
the Donors of the American Chemical Society Petroleum Research
Fund for support of this research. Y.T. thanks the the Global COE
Program (Project No. B01: Catalysis as the Basis for Innovation in
Materials Science) from the Ministry of Education, Culture, Sports,
Science and Technology (Japan). We thank Prof. Matt Sigman and
Prof. Jon Rainier for insightful discussions.
AgI catalysis proved to be optimal for the generation of 3a
with AgOAc giving a 1: > 20 ratio of 2a:3a in 55% yield
(Table 1, entry 4). It was further found that addition of AcOH
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006087.
684
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Angew. Chem. Int. Ed. 2011, 50, 684 –687

Table 2: Substrate scope for the hydroamination of propargylguanidines
with [Rh2(oct)4] or AgOAc as catalyst.
to the AgOAc-catalyzed reaction gave significant rate
enhancements (Table 1, entry 5) suggesting that protonolysis
of the vinyl metal species was rate limiting, consistent with the
known electrophilic hydroamination mechanism.[13] Our first
success in reversing the selectivity was found with gold(III)
catalysts that favored the 6-endo product (Table 1, entries 6
and 7). The sluggishness of the Au-catalyzed reactions
directed our attention to RhII. Dirhodium(II) carboxylates
have rarely been used to activate alkynes,[14] however Murai
et al. have shown that [Rh2(tfa)4] is a competent ene–ene–yne
cycloisomerization catalyst and gives different product dis-
tributions than PtII or RuII.[15] Gratifyingly, [Rh2(tfa)4] turned
the selectivity over favoring the 6-endo product (Table 1,
entry 8). Quite to our surprise, given its decreased Lewis
acidity, [Rh2(OAc)4] was a very selective catalyst favoring the
6-endo product 13:1 (Table 1, entry 9). The reaction times
were long and we suspected that this was due to catalyst
solubility. The reaction was enhanced with [Rh2(oct)4] giving
the 6-endo product in 81% yield after 16 h in > 20:1 (2a:3a)
selectivity (Table 1, entry 10).
Entry Substrate
Catalyst
Yield Select. 6-endo
[%][a] 2:3
product 2
[Rh2(oct)4] 92
AgOAc 65
>20:1
1:2
1
[Rh2(oct)4] 60
AgOAc 80
5:1
1:>20
2
3
[Rh2(oct)4] 95
AgOAc 90
>20:1
1:2
Having identified a selective catalyst set, a substrate
selectivity profile was developed for the reaction (Table 2)
and it was immediately apparent that the reactivity of the
dirhodium(II) carboxylates was quite unique. For example,
cyclization of the p-methoxyphenyl alkyne (Table 2, entry 1)
with AgI favored the 5-exo product, however with poor
selectivity, consistent with the ability of this substituent to
competitively stabilize a vinyl cation for 6-endo cyclization. In
contrast, RhII gave exclusively the 6-endo product 2b.
Cyclization of electron-poor aryl alkynes showed the opposite
trend, with AgI giving high 5-exo selectivity while RhII was
more modestly selective for the 6-endo product 2c (Table 2,
entry 2). Alkyl-substituted alkynes gave the 6-endo products
exclusively with RhII (Table 2, entries 3–7). This is in direct
contrast to the AgI-catalyzed reactions, where modest selec-
tivities for the 5-exo products are seen when the alkyne
termini are electronically indistinguishable. Importantly for
subsequent annulations and access to polycyclic skeletons,
[Rh2(oct)4] tolerates useful functional groups (e.g. alcohols
and alkyl chlorides, Table 2, entries 4–7). These primary alkyl
chlorides were also cleanly cyclized to the 5-exo-dig isomers
2g,h with AgI. Substitution is also permitted at the prop-
argylic position wherein good selectivities are seen with AgI
for the 5-exo product and with RhII for the 6-endo product
(Table 2, entry 8). Substituents on the guanidine nitrogen had
modest effects on selectivity, with the 6-endo product always
favored under RhII catalysis (Table 2, entries 9,10). The tert-
butyl alkyne 1l (Table 2, entry 11) reacted well in the AgI-
catalyzed process but was unreactive toward RhII, presumably
due to the size of the RhII catalyst.
[Rh2(oct)4] 95[b] >20:1
4
5
6
7
AgOAc
65
1:2
[Rh2(oct)4] 95
AgOAc 60
>20:1
1:3
[Rh2(oct)4] 98
AgOAc 55
>20:1
1:5
[Rh2(oct)4] 80
AgOAc 63
>20:1
1:7
[Rh2(oct)4] 41
AgOAc 95
12:1
1:>20
8
[Rh2(oct)4] 68
AgOAc 71
7:1
1:>20
9[c]
10
[Rh2(oct)4] 68
AgOAc 71
11:1
1:2
The resultant cyclic ene-guanidines contain a rich func-
tional group handle for further manipulations (Scheme 1).
For example bromination proceeds to give the 5-bromodihy-
dropyrimidine 5 the structure of which was further confirmed
by X-ray crystallography (Scheme 1a). Oxidative cyclization
of pendant nucleophiles gives the spirocyclic hemiaminal 6,
reminiscent of the crambescidins Scheme 1b. Deprotection of
the 5-membered ene-guanidine 3a under acidic conditions
was accompanied by isomerization to give the 2-amino-
[Rh2(oct)4] n.d.
AgOAc 70
–
1:11
11
[a] Yields of isolated product. [b] Products were inseparable by chroma-
tography; combined yield. [c] PMB=p-methoxybenzyl.
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685

Communications
scenario wherein the initial cyclization to form a 5- or 6-
membered vinyl–rhodium anion is highly reversible and that
perturbation of this pre-equilibrium by stabilizing the kineti-
cally favored 5-exo-dig intermediate leads to poor selectiv-
ity.[20]
Mechanistically it is difficult to rationalize oxidation state
changes in the dirhodium(II) carboxylates upon arriving at a
vinyl–rhodium intermediate (in this case the formation of RhI
in the dimer). This prompted us to examine better defined
catalysts known to proceed through vinyl–rhodium inter-
mediate.[21] Although sluggish, Wilkinsonꢀs catalyst promoted
the cyclization and favored the 6-endo product in 10:1
selectivity (Table3, entry 4). Cationic RhI, however, reversed
the selectivity favoring the 5-exo product in 10:1 selectivity
(Table3, entry 5). Again this may support the necessity for the
initial cyclization event to be reversible in order to access the
6-endo product. More importantly this suggests access to
more defined vinyl–rhodium intermediates that might be
exploited for cascade reactivity.
Scheme 1. Transformations of the resultant ene-guanidines. PMP=p-
methoxyphenyl, NBS=N-bromosuccinimide.
In conclusion we have demonstrated the unique ability of
dirhodium(II) carboxylates to catalyze the 6-endo-dig selec-
tive hydroamination of propargylguanidines. The resultant
cyclic ene-guanidines contain a rich latent functional group
for the preparation of skeletally diverse cyclic guanidine
natural product substructures. Studies to further understand
the reactivity of dirhodium(II) carboxylates and the applica-
tion of these products to more complex targets are ongoing
and will be reported in due course.
imidazole 7 (Scheme 1c).[16] Reduction was also cleanly
performed on 2a to give tetrahydropyrimidine
8
(Scheme 1d).
Examples of alkyne activation by dirhodium(II) carbox-
ylates are quite rare.[8,17] Given the fact that reactions of
internal alkynes have only been observed with [Rh2(tfa)4],[18]
and that [Rh2(oct)4] is not able to activate alkynes independ-
ently,[8] we were surprised that the dirhodium(II) alkylcar-
boxylates were competent catalysts for this transformation
especially at room temperature.[19] This was especially true for
the cyclization of electron-deficient alkynes such as the
pCF3Ph-substituted alkyne 1c. We were even more surprised
by the observation that 1c reacted ten times faster than the p-
methoxy-substituted alkyne 1b. Regardless of the poor p-
Lewis acidity of these catalysts, this suggested that coordina-
tion of the alkyne was not rate limiting. Addition of 3
equivalents of acetic acid changed the selectivity from 5:1 to
1:1.7 (2c:3c, Table 3, entries 1 and 2) suggesting that proto-
nation of a vinyl–rhodium intermediate might be involved in
the product-determining step. The use of [Rh2(tfa)4] as a
catalyst also favored the 5-exo-dig product with 1c (Table 3,
entry 3). Taken together this may suggest a Curtin–Hammett
Received: September 28, 2010
Published online: December 9, 2010
Keywords: alkyne activation · guanidine · heterocycles ·
.
hydroamination · rhodium
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pCF3Ph [Rh2(oct)4]
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pCF3Ph [Rh2(tfa)4]
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10:1
1:10
Ph
Ph
[(Ph3P)3RhCl] CH2Cl2, 608C, 12 h
[(Ph3P)3RhCl] AgSbF6, CH2Cl2, RT, 12 h
[a] 3 equivalents of AcOH were used.
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Angew. Chem. Int. Ed. 2011, 50, 684 –687
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