Gold-Catalyzed Aminoalkenylation of β-Amino-1,n-Diynols to Cycloalkyl-, Piperidinyl- and Pyranyl-Fused Pyrroles

Article abstract of DOI:10.1002/adsc.201600011

A synthetic method to prepare cycloalkyl-, piperidinyl- and pyranyl-fused pyrroles efficiently by gold(I)-catalyzed dehydrative aminoalkenylation of β-amino-1,n-diynols under mild conditions at room temperature is described.

Full text of DOI:10.1002/adsc.201600011

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DOI: 10.1002/adsc.201600011
Very Important Publication
Gold-Catalyzed Aminoalkenylation of b-Amino-1,n-Diynols to
Cycloalkyl-, Piperidinyl- and Pyranyl-Fused Pyrroles
Prasath Kothandaraman,c Yichao Zhao,a Bo Ra Lee,a Clarrisa Jia Le Ng,c
Jun Yi Lee,c Benjamin James Ayers,c and Philip Wai Hong Chana,b,*
a
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
Fax: (+61)-3-9905-4597; e-mail: phil.chan@monash.edu
Department of Chemistry, University of Warwick, Coventry, CV4 7AL, U.K.
b
E-mail: P.W.H.Chan@warwick.ac.uk
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
c
University, Singapore 637371, Singapore
Received: January 5, 2016; Revised: February 14, 2016; Published online: April 25, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600011.
À
À
Abstract: A synthetic method to prepare cycloalk-
yl-, piperidinyl- and pyranyl-fused pyrroles effi-
ciently by gold(I)-catalyzed dehydrative aminoalke-
nylation of b-amino-1,n-diynols under mild condi-
tions at room temperature is described.
C N rather than C C bond formation might instead
prevail to give the putative (4,5-dihydro-1H-pyrrol-3-
yl)gold species I.[4,8–10] Subsequent dehydrative aroma-
tization followed by trapping of the ensuing cycload-
duct by the remaining alkyne moiety may then be an-
ticipated to deliver pyrrole-containing bicyclic mole-
cules 2–8 in a straightforward manner.[11–14] Achieved
under mild conditions at room temperature, we
report herein the realization of this unprecedented
aminoalkenylation chemistry in gold catalysis that
provides a facile and chemoselective approach to cy-
cloalkyl-, piperidinyl- and pyranyl-fused pyrroles in
Keywords: 1,2-amino alcohols; gold; homogeneous
catalysis; nitrogen heterocycles; synthetic methods
Functionalized pyrroles are present as a structural good to excellent yields and as single regioisomers.
motif in many bioactive natural products and pharma- Our present study began by examining the gold-cat-
ceutically interesting compounds.[1,2] They also feature alyzed cycloisomerizations of b-amino-1,6-diynol 1a in
in many optoelectronic functional materials and are order to establish the reaction conditions (Table 1).[15]
versatile building blocks in organic synthesis and drug This initially revealed that treating the substrate with
discovery programs. For this reason, the development 5 mol% of gold(I) phosphine catalyst A in THF at
of facile catalytic methods for pyrrole synthesis with room temperature for 1 h afforded piperidinyl-fused
selective control of substitution patterns by using pyrrole 2a in 70% yield (entry 1). The structure of the
readily accessible substrates continues to be actively nitrogen-containing cycloadduct was determined by
pursued.
NMR spectroscopic measurements and X-ray crystal-
Gold-catalyzed alkyne cycloisomerizations have lography.[16] Lower product yields of 14–60% were ob-
come to represent one of the most efficient synthetic served when the transformation was conducted with
methods for rapidly increasing molecular complexity the gold(I) phosphine complex B, AuCl and AuCl3 as
and diversity.[3–6] In the last decade, the field has ex- the catalyst (entries 2, 10 and 11). An increase in
panded exponentially, with a myriad of elegant ap- product yield from 70 to 82 to 90% was subsequently
proaches to synthetically valuable compounds being achieved when the reaction was repeated with
established. Included in this has been the recent emer- Ph3PAuCl/AgOTf and Ph3PAuNTf2 in place of gold(I)
gence of a small handful of examples describing the complex A as the catalyst (entries 4 and 5). With
assembly of 1- and 2-naphthyl ketones, phenanthrenes Ph3PAuNTf2 as the catalyst, changing the solvent
and 8H-indeno[1,2-c]furans from the corresponding from THF to acetone, toluene, dichloromethane or
1,n-diynols [Scheme 1, Eq. (1)].[6,7] We envisioned that 1,2-dichloroethane led to 2a being obtained in yields
if 1,n-diynols bearing an appropriately placed b- of 52–98% (entries 6–9). However, no reaction was
amino group were explored, such as the type 1 shown detected in control experiments catalyzed by the
in Scheme 1, Eq. (2), a reaction sequence initiated by gold(I) phosphine complex C or 10 mol% of the
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Prasath Kothandaraman et al.
Scheme 1. Gold-catalyzed reactivities of 1,n-diynols.
Brønsted acids TfOH or Tf2NH (entries 3, 13 and 14). ucts, in 2:1 and 1:1 ratios, and in 67 and 69% yield, re-
In a final control reaction mediated by 5 mol% of spectively. An increase in the product yield of the 5n
AgOTf with THF as the solvent, the exclusive forma- and 7n mixture to 88%, and that of 5o and 7o to
tion of the monocyclic pyrrole 9a in 80% yield was 85%, was observed when the reaction time was in-
found (entry 12). On the basis of the above results, creased from 1 to 3 h. A slight fine-tuning of the con-
the procedure described in entry 6 with 5 mol% of ditions in the analogous experiments of these sub-
Ph3PAuNTf2 as the catalyst in acetone at room tem- strates with the introduction of 4Š molecular sieves
perature for 1 h was deemed to provide the optimum (MS) for 2 h subsequently led to the exo-alkenylated
reaction conditions.
pyrroles 7n and 7o being chemoselectively afforded in
With the reaction conditions established, we next respective yields of 89 and 94%. Likewise, in the pres-
sought to evaluate the generality of the methodology ence of 4Š MS, the exo-alkenylated pyrroles 8p–
for a series of b-amino-1,n-diynols 1b–s. As illustrated s were exclusively provided from the corresponding
in Table 2, we found the reaction conditions to be b-amino-1,7-diynols 1p–s in 85–93% yield. Intriguing-
broad, with a variety of substituted fused-pyrroles 2–8 ly, repeating the reactions of these substrates 1p–s in
furnished in 52–96% yield. Starting b-amino-1,6-diyn- the absence of 4Š MS gave the endo-alkenylated pyr-
ols (1b–e) bearing alkyl or aryl substituents at the car- roles 6p–s as the sole adduct. The structure of the cy-
binol carbon center were found to react well to afford cloheptenyl-fused pyrrole 6r was ascertained by NMR
the corresponding piperidinyl-fused pyrrole adducts spectroscopic measurements and X-ray crystallogra-
2b–e in up to 95% yield. Likewise, comparable prod- phy.[17]
uct yields of 92 and 83% were obtained in the reac-
The mechanistic premise outlined in Scheme 1, Eq.
tion of substrates bearing two adjacent phenyl groups (2), predicted that the gold(I)-catalyzed cycloisomeri-
(1f) or an ethereal diyne linker (1h). The only in- zation may proceed through an aminoalkenylation
stance where a lower product yield of 52% was ob- pathway comprised of tandem hydroamination and al-
tained is when the b-position of the substrate bore an kenylation steps. While the isolation of 9a in Table 1,
aliphatic isopropyl moiety (1g). The reaction of b- entry 12, under catalysis by AgOTf was fortuitous, the
amino-1,5-diynols (1i–m) containing a -(CH2)2- teth- outcome suggests that this may be an intermediate in
ered diyne also furnished the corresponding cyclohex- the gold(I)-catalyzed transformation. This was corro-
enyl-fused pyrroles 4i–m in up to 78% yield. The b- borated by the formation of fused-pyrrole 2a in 96%
amino-1,6-diynol homologues 1n and 1o were initially yield from the aromatic N-heterocycle under the opti-
found to afford mixtures of 5n and 7n, and 5o and 7o mized gold(I) catalysis conditions [Scheme 2, Eq. (1)].
of the corresponding endo- and exo-alkenylated prod- The likelihood of this catalytic reaction pathway was
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Gold-Catalyzed Aminoalkenylation of b-Amino-1,n-Diynols
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
2a [%][b]
1
2
3
A
B
C
THF
THF
THF
70
60
–
[c]
4
5
6
7
8
9
10
11
12
13
14
Ph3PAuCl/AgOTf
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
AuCl
THF
THF
82
90
98
92
82
52
27
14
Scheme 2. Control experiments with 1p and 9a.
acetone
toluene
CH2Cl2
(CH2Cl)2
THF
THF
THF
THF
THF
3-ol adduct III would deliver isolable pyrrole 9 via
the iminium species IV.[10] Further activation of the
pendant alkyne in this newly formed compound may
afford the gold(I)-coordinated complex V. In the in-
stances of 1,5-diynol substrates (1i–m), this may lead
to 5-endo-dig alkenylation to the spirocyclic gold spe-
cies VI and subsequent 1,2-alkyl migration to give the
second vinyl gold intermediate VII.[13] Rearomatiza-
tion and protodemetallation would then furnish the
cyclohexenyl-fused adduct 4. In contrast, 1,6- and 1,7-
diynol substrates (1a–h and 1n–s) may undergo the re-
spective preferential 5-exo-dig and 6-exo-dig cycliza-
tions to produce spirocyclic vinyl gold adduct VIII
from Au(I)-activated complex V. Subsequent 1,2-alkyl
migration of this adduct to give the bicyclic gold spe-
AuCl3
AgOTf[d]
Tf2NH[d]
TfOH[d]
–
–
[e]
[c]
[c]
–
[a]
All reactions were performed on the 0.18 mmol scale
with catalyst:1a ratio=1:20 at room temperature for 1 h.
Isolated yield.
No reaction based on TLC and H NMR analysis of the
crude mixture.
Reaction performed with 10 mol% of the catalyst.
Compound 9a obtained in 80% yield.
[b]
[c]
1
[d]
[e]
further exemplified by the isolation of 9p on repeat- cies IX followed by rearomatization and protodeme-
ing the Au(I)-mediated rearrangement of b-amino- tallation would deliver the exo-alkenylated pyrroles 2,
1,7-diynol 1p under the conditions described in 3, 7 and 8. For the piperidinyl- and pyranyl-fused ad-
Scheme 2, Eq. (2) for 3 h. Resubmission of the pyr- ducts 2 and 3, we propose that stabilization through
role intermediate to the same reaction conditions for non-conjugation of the heteroatom lone pair may ra-
a further 18 h afforded the fused-pyrrole adduct 8p in tionalize the exclusive isolation of these exo-al-
90% yield. In contrast, repeating the analogous trans- kenes.[18] However, without this heteroatomic interac-
formation of 9p with 5 mol% of Tf2NH instead of tion, the greater stability offered by an internal
Ph3PAuNTf2 as the catalyst was found to the near alkene moiety may explain the isolation of pyrroles 7
quantitative recovery of the pyrrole substrate.
and 8, and isomerization to the endo-tautomers 5 and
A tentative mechanism for the present gold(I)-cata- 6 under the mild acidic conditions generated in the
lyzed aminoalkenylation of b-amino-1,n-diynols is presence of water. A redistribution of product iso-
outlined in Scheme 3. We postulate that this could in- mers in control experiments with the exo-alkenylated
volve the initial activation of the internal alkyne pyrrole 8p under the various conditions described in
moiety in the substrate to give the organogold com- Scheme 4 would support this latter posited role of
plex II. This might consequently trigger the formation water. Treatment of 8p with an equivalent of water
À
of vinyl gold intermediate I by an intramolecular C
for 18 h was found to give a 1:1 mixture of 6p and 8p,
N bond-forming hydroamination step. Ensuing proto- which was observed to further increase to 11:1 on re-
demetallation and Brønsted acid-assisted dehydrative peating the reaction with an extended reaction time
aromatization of the resultant 2,3-dihydro-1H-pyrrol- of 48 h. A similar outcome was achieved after 18 h
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Prasath Kothandaraman et al.
Table 2. Aminoalkenylation of b-amino-diynols 1b–s catalyzed by Ph3PAuNTf2.[a]
[a]
All reactions were performed on the 0.18 mmol scale with a Ph3PAuNTf2:1 ratio of 1:20
in acetone at room temperature for 1 h. Values in parentheses denote isolated yields and
product ratios for mixtures.
Reaction conducted in toluene at 808C.
Reaction time=2 h.
Reaction time=3 h.
Reaction with 4 Š MS.
Reaction time=18 h.
[b]
[c]
[d]
[e]
[f]
when the control experiment was repeated in the on the possible mechanistic pathway, supporting
À
À
presence 5 mol% of Ph3PAuNTf2 with the endo- and a tandem C N/C C bond forming sequence, and
exo-alkenylated pyrroles being obtained in a ratio of a gold-mediated isomerization of the alkenylated
17:1. Likewise, the analogous reaction with 5 mol% of products formed. The substrate scope proved to be
Tf2NH in place of Ph3PAuNTf2 as the catalyst was general, furnishing a range of functionalized pyrroles
found to give a 4:1 distribution of 6p and 8p. In con- which may be of interest in both pharmaceutical and
trast, a ratio of 12:1 in favour of the disubstituted materials chemistry.
alkene product was observed on conducting the iso-
merization process for a final time with 5 mol% of
Ph3PAuNTf2 and 5 mol% of K2CO3.
Experimental Section
In summary, we have described an efficient synthet-
ic strategy to diversely functionalized cycloalkyl-, pi-
peridinyl- and pyranyl-fused pyrroles by aminoalkeny-
General Procedure
lation of b-amino-1,n-diynols. The observed results
and isolation of the pyrrole intermediates shed light (4.7 mmol) was added a solution containing 1 (0.18 mmol) in
To
a stirred acetone (1 mL) solution of Ph3PAuNTf2
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Gold-Catalyzed Aminoalkenylation of b-Amino-1,n-Diynols
Scheme 3. Proposed mechanism for the gold(I)-catalyzed aminoalkenylation of b-amino-1,n-diynols.
acetone (1 mL) in a drop-wise manner at room temperature
under atmospheric conditions (for substrates 1i–s, the reac-
tion was stirred at 808C and 4Š MS (100 mg) were added
for substrates 1p–s). The reaction progress was monitored
by TLC analysis to completion. The reaction mixture was
then quenched with saturated NaHCO3 (2 mL) and extract-
ed with EtOAc (2”25 mL). The organic layer was then
washed with brine (20 mL), dried over Na2SO4, filtered, con-
centrated under reduced pressure and purified by flash
column chromatography (eluent: n-hexane/EtOAc=6:1) to
afford the desired product.
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Acknowledgements
This work was supported by a Discovery Project Grant from
the Australian Research Council (DP160101682). We thank
Dr. Yongxin Li (Nanyang Technological University) for pro-
viding the X-ray crystallographic data reported in this work.
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Adv. Synth. Catal. 2016, 358, 1385 – 1391
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