Gold-Catalyzed [2,3]-Sigmatropic Rearrangement: Reaction of Aryl Allyl Alcohols with Diazo Compounds

Article abstract of DOI:10.1021/acs.orglett.6b03836

A gold-catalyzed [2,3]-sigmatropic rearrangement reaction has been developed. The intermolecular rearrangement occurs between in situ generated donor-acceptor gold-carbenes and cinnamyl alcohols via tandem oxonium ylide formation. The desired rearranged product has been accomplished selectively over more conventional O-H insertion, cyclopropanation, cycloaddition, and C-H functionalization products under mild, open-air conditions. The scope of the work has been illustrated by synthesizing a new class of substrates that can be used for constructing complex molecular targets.

Full text of DOI:10.1021/acs.orglett.6b03836

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed [2,3]-Sigmatropic Rearrangement: Reaction of Aryl
Allyl Alcohols with Diazo Compounds
Santhosh Rao and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
S
* Supporting Information
ABSTRACT: A gold-catalyzed [2,3]-sigmatropic rearrangement reaction has been developed. The intermolecular rearrange-
ment occurs between in situ generated donor−acceptor gold−carbenes and cinnamyl alcohols via tandem oxonium ylide
formation. The desired rearranged product has been accomplished selectively over more conventional O−H insertion,
cyclopropanation, cycloaddition, and C−H functionalization products under mild, open-air conditions. The scope of the work
has been illustrated by synthesizing a new class of substrates that can be used for constructing complex molecular targets.
Scheme 1. Gold-Catalyzed [2,3]-Sigmatropic Reaction
old, once considered as the “lethargic and overweight
Gversion of catalytically interesting copper”, is today
regarded as one of the most versatile metals with rich chemistry.1
Influenced by relativistic effects,2 it exhibits increased “π acidity”
and “electron delocalization”. These two features result in a dual
“push−pull” reactivity which has opened exciting new avenues in
synthetic organic chemistry.3 In this direction, gold has been
successfully used to catalyze carbene transfer reactions,3c such as
heteroatom−H (such as O, N) insertion,4 cyclopropanation5/
cyclopropenation,6 C−H functionalization,4,7 and cycloaddition
reactions.17
The gold-catalyzed carbene transfer reaction is relatively
recent, and a seminal report by Nolan and Per
́
ez4 showed that
gold can indeed form gold−carbenes to mediate carbene-transfer
reactions (Scheme 1).8 The ability of carbenes/carbenoids to
form ylides with Lewis bases (B:), such as ethers, sulfides, amines,
and carbonyls, had a profound influence on the development of
diazocarbonyl compounds as synthetic precursors.9 Ylides, other
than simple heteroatom−H insertions, formed during carbene-
transfer reactions can also undergo [2,3]-sigmatropic rearrange-
ment, [1,2]-shift (Stevens rearrangement), and related reac-
tions.8a Guiding the reaction to the desired [2,3]-sigmatropic
rearranged product, selectively, is pertinent and will provide great
synthetic advancement by forming C−C or C−heteroatom
bonds in asingle step (Scheme 1).10 Generating an oxonium ylide
is also challenging, compared to conventional N or S stabilized
ylides, due to its inherent instability.8,10 In this direction, the Rh-
catalyzed [2,3]-sigmatropic reaction by Doyle10 and an intra-
molecular allylic ether oxonium ylide derived [2,3]-sigmatropic
reaction using Rh11 by Pirrung and Johnson, paved the way
forward. An enantioselective [2,3]-sigmatropic reaction between
highly substituted allyl alcohols and donor/acceptor carbenoids,
developed by Davies, further empowered the synthetic utility of
the rearrangement.12 However, this limits the scope of the
reaction to only secondary and tertiary alcohols. More common
primary allyl alcohols cannot be used to achieve the desired
product. As demonstrated by Hu et al.,13 a simple cinnamyl
alcohol under similar reaction conditions does not lead to the
[2,3]-sigmatropic rearranged product but affords the correspond-
ing O−H insertion product. Stringent reaction requirements and
competitive O−H/C−H insertions with Rh catalysts further
complicate the reaction.9,13 Recently, Yang and Tang reported
Received: December 24, 2016
© XXXX American Chemical Society
A
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Letter
NHC−Au-catalyzed intramolecular [2,3]-rearrangement of
allylic oxonium ylides derived from allylic ethers and alkyne as
carbene precursors.14 Allylic sulfides have also been employed for
generating corresponding ylides from alkyne precursors to
undergo [2,3]-rearrangement.15 Achieving [2,3]-sigmatropic
rearragement of simple allyl alcohols is challenging and
unprecedented due to the instability of corresponding oxonium
ylides.
Au from the reaction system yielded no desired product but a
complexcrudereactionmixturecomprisingmainlyofdiazodimer
byproduct. This disregarded the direct role of Ag, if any, in
obtaining the desired rearranged product (Table 1, entry 3).19 As
a consequence of the relativistic effects,2 the influence of the
phosphine ligand in altering the bonding and reactivity of the
gold−carbene complex reactivity is relatively more pronounced
due to the increased covalent character between Au−P bonds.2,20
To verify this hypothesis, AuCl, devoid of a ligand (PPh3), was
used, which gave only O−H insertion product in major amount
(67%) along with other minor unidentified impurities (Table 1,
entry 4). This clearly indicated the necessity of the ligand in
guiding the reaction to the [2,3]-sigmatropic rearranged product.
Increasing or decreasing the catalyst loading reduced the yield of
rearranged product 3aa to 15 and 41%, respectively (entries 5 and
7). Solvent screening results showed Et2O as the best solvent
(Table 1, entry 6. For more details, see Tables S1 and S3,
Supporting Information). A brief screening of Ag salts identified
AgNTf2 as the best halide scavenger (Table 1, entries 8−11).
Using IPr as a ligand gave only the O−H insertion product,
indicating that the electron-rich strong σ-donor NHC ligand was
not suitable for the desired transformation (Table 1, entry 12).
Based on the promising outcome shown by PPh3, we envisaged
thathavingabulkyPCy3 ligandwitharelativelyweakerπ-acceptor
character would greatly facilitate the reaction by inducing the
required carbenoid type of reactivity. The reason may be
attributed to an increased electron back-donation from Au
stabilizing the carbenic carbon as well as the oxonium ylide
intermediate for the subsequent rearrangement.21 Gratifyingly,
the desired rearranged product 3aa was obtained in 91% yield
(based on 1H NMR, entry 13). Further optimization with respect
to the catalyst amount and the reaction time (entries 14 and 15)
provided theoptimalconditions forthepresentreaction(Table1,
entry 15). It is also noteworthy that PCy3AuCl was efficient in
increasing thediastereoselectivity (96:4) compared toPPh3AuCl,
suggesting a possible association of the catalyst to the ylide in the
final product-forming step.
With the optimal conditions established, we studied substrate
scope by reacting cinnamyl alcohol with a variety of α-aryl-α-
diazoacetates (Scheme 2).22 As expected, diazo esters comprising
ethyl, methyl, and isopropyl groups had no significant effect on
the outcome of the reaction and gave 3aa, 3ab, and 3ac in 72, 91,
and 71%, respectively (Scheme 2). However, varying substituents
on the aromatic group of the diazo compound resulted in a
considerable change in the yield of the desired products. Thus,
both steric as well as electronic factors played a major role in the
reaction outcome as illustrated in the examples (Scheme 2, 3ad−
ag). Substituents such as −OMe and −OTs on the aromatic
group of the diazo compound gave excellent yields (3ad and 3ae,
87 and 80%, respectively). Ethyl p-chlorophenyldiazoacetate gave
43% of the expected product (3af) along with the O−H nsertion
product in 56% yield (1HNMR yield), whereas an o-chloro
substitution did not give the expected product (Scheme 2, 3ag)
but furnished only the O−H insertion product (74%, Scheme 2,
4ag), which may be attributed to an unfavorable steric effect (see
Scheme 4).
Inspired by the relativistic effect,2 we envisioned that cationic
gold may be used to accomplish the desired [2,3]-sigmatropic
reaction. PPh3AuCl along with AgSbF6 (halide scavenger) was
chosen as the initial catalytic system for the following reasons: (i)
ability to form electrophilic gold-carbene; (ii) possible stabiliza-
tion of the cation by backbonding;2 (iii) controlling the
stereoselectivity;2 and (iv) possible modulation of the nature of
gold-carbenes by the ligand variation.16 Cinnamyl alcohol (1a)
and ethyl phenyldiazoacetate (2a) were chosen as the standard
substrates. Under the given conditions, cinnamyl alcohol was an
interesting but challenging substrate considering its susceptibility
toward probable cyclopropanation,5,6 O−H insertion,4,13 C−H
functionalization,7 and cycloaddition reactions.17 However, after
a few initial screening reactions, we were delighted to observe the
desired rearranged product 3aa in a complex crude reaction
mixture, albeit in only 22% isolated yield (Table 1, entry 1). The
result promised a new class of compounds that can be accessed.
The structure of 3aa was unambiguously confirmed by X-ray
crystallography study.18
a
Table 1. Optimization of the Reaction Conditions
b
c
b
entry
catalyst
3aa yield (%)
dr
4aa yield (%)
1
2
3
4
PPh3AuCl/AgSbF6
PPh3AuCl
45 (22)
nr
89:11
35
AgSbF6
nd
AuCl/AgSbF6
nd
67
27
18
19
d
5
PPh3AuCl/AgSbF6
PPh3AuCl/AgSbF6
PPh3AuCl/AgSbF6
PPh3AuCl/AgOAc
PPh3AuCl/AgBF4
PPh3AuCl/AgOTf
PPh3AuCl/AgNTf2
IPrAuCl/AgNTf2
PCy3AuCl/AgNTf2
PCy3AuCl/AgNTf2
PCy3AuCl/AgNTf2
15
90:10
85:15
35:6
6
58
e
7
41
8
nr
9
trace
60 (48)
67
13
10
11
12
13
95:5
96:4
40
14
trace
91
46
97:3
97:3
96:4
trace
trace
trace
f
14
93
g
15
96 (72)
a
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst (1.5 mol
%), solvent (entries 1−5, DCM, 2 mL; entries 6−15, Et2O, 3 mL), rt,
b
1
12 h. Measured by H NMR with terephthalaldehyde as the internal
standard, nr = no reaction, nd = not detected. The numbers in
c
parentheses are isolated yields. dr = diastereomeric ratio of 3aa.
d
e
f
g
catalyst = 5 mol %. catalyst = 1 mol %. catalyst = 2 mol %. catalyst
= 3 mol %.
Proceeding further, a variety of cinnamyl alcohols were reacted
with methyl phenyldiazoacetate (2a, Scheme 3) to afford
moderate to excellent yields of the rearranged products in 32−
95% yields. As can be seen, alkyl substituents on the aromatic ring
resulted in the formation of the required product in excellent
yields (Scheme 3, 3bb−db). The remarkable selectivity observed
in these rearrangement reactions is noteworthy, whereas Au-
With this promising result (entry 1), weproceeded further with
the optimization reactions. Excluding the halide scavenger in the
reaction (AgSbF6) did not furnish the expected product, but both
the starting materials remained intact. This reaction clearly
indicates the necessity of a noncoordinating counterion to
activate the cationic gold (Table 1, entry 2). Further, eliminating
B
DOI: 10.1021/acs.orglett.6b03836
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Letter
was not successful in affording the rearranged product 3ib, which
may be due to the quenching of the gold complex. Substrates with
electron-withdrawing groups such as −NO2 and −CF3 reacted
well to give moderate yields of the rearranged products, 3jb and
3kb in 32 and 45% yield, respectively (Scheme 3). Halide
substituents were also found to react smoothly to give the desired
product in moderate to excellent yields (Scheme 3, 3lb−pb, 45−
78%). The reaction of (E)-3-(pyridin-2-yl)prop-2-en-1-ol with
2b was unsuccessful in furnishing the product 3qb.
Scheme 2. Scope of the α-Aryl-α-diazoacetates
Based on the literature precedence,8 and the obtained product
structure, agenerictransitionstatehasbeenproposed(Scheme4)
Scheme 4. Generic Transition-State Analysis
a
Measured by 1H NMR (terephthalaldehyde: internal standard).
b
Numbers in parentheses are isolated yields. dr = diastereomeric ratio.
Scheme 3. Scope of the Allyl Alcohols
as a result of Au associated ylide system. As can be construed, the
TS2 is expected to have relatively higher energy than the TS1 due
to the potential steric interaction between the adjacent aryl rings
resulting in the selective formation of 3aa as the major
diastereomer.
To understand the reactivity of gold−carbene complexes, an
investigation was performed using electronically dissimilar
substrates (Table 2). Effect of the presence of a methyl group at
Table 2. Deviation from the Standard Substrates
a
Measured by 1H NMR (terephthalaldehyde: internal standard).
b
Numbers in parentheses are isolated yields. dr = diastereomeric ratio.
c
3gb decomposed during isolation.
a
Entries 1−6: 1 (0.5 mmol), 2a (1 mmol). Entries 7−8: 1a (0.5
b
mmol), 2 (1 mmol). Measured by 1H NMR with terephthalaldehyde
as the internal standard. Isolated yields are in parentheses. dr =
c
catalyzed reactions are well-known to provide benzylic CH-
functionalized products.4,7d An o-methyl group on the aryl
system, considering the relative proximity to the carbene center,
had a negligible effect on the reaction outcome (3db, 73%).
Similarly, a naphthyl substituent on the allyl alcohol also resulted
in 79% of the product (3eb). An aryl ring with electronically rich
substituents resulted in moderate to excellent yields (Scheme 3,
3fb and 3hb, 49 and 72% respectively). The reaction of cinnamyl
alcoholderivative containingp-NMe2 substitutiononthearylring
diastereomeric ratio.
the 1-, 2-, or 3-positions of the 3-phenylallyl alcohols (1a) was
probed, which has shown a significant change in the outcome of
the reaction (entries 1−3, Table 2). Using 1-methyl-3-phenylallyl
alcohol gave the desired product 3rb in moderate yield (31%).
Whereas 2-methyl-3-phenylallyl alcohol and 3-methyl-3-phenyl-
allyl alcohol did not furnish the rearranged products but afforded
C
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(5) Au catalyzed cyclopropanation: Prieto, A.; Fructos, M. R.; Díaz-
OH insertion products 4sb and 4tb in 94 and 68% yields,
respectively. Similarly, 1-phenyl-substituted 3-phenylallyl alcohol
gave a moderate yield of the expected product (3ub, 21%, entry
4). A vinyl extension of the allyl alcohol also gave the expected
product 3vb in moderate yield (22%, entry 5). However, as can be
seen in entry 6, lack of an aryl system resulted only in the
formation of the O−H insertion product 3wb in excellent yield
(88%). Conversely, employing acceptor−acceptor carbene
precursors resulted in no reaction, and both of the starting
materials were intact (entry 7). However, using an acceptor
carbenegave the O−H insertion product ingood yield(4ah, 62%,
Table 2, entry 8), which emphasizes the requirement of the
donor−acceptor nature of the carbene precursor.
Insummary, wehavedevelopedahomogeneousgold-catalyzed
intermolecular [2,3]-sigmatropic rearrangement reaction be-
tween in situ generated donor−acceptor gold−carbenes and
cinnamyl alcohols. The method generates an oxonium ylide
followed by [2,3]-sigmatropic rearrangement, competing favor-
ably with the more conventional O−H insertion, cycloaddition,
cyclopropanation, Stevens rearrangement, and C−H functional-
izationreactions under mildopen-air conditions withouttheneed
for syringe pumps or related sophisticated delivery methods. We
are at present pursuing enantioselective versions of the present
methodwhichmaybeusedinbuildingcomplexmoleculartargets.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b03836.
Experimental procedures, characterization data, and
spectra for all compounds (PDF)
Crystal structure of 3aa (CIF)
(14) NHC-Au catalyzed intramolecular [2,3]-rearrangement of allylic
oxonium ylides: Fu, J.; Shang, H.; Wang, Z.; Chang, L.; Shao, W.; Yang,
Z.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52, 4198−4202.
(15) NHC-Au catalyzed intramolecular [2,3]-rearrangement of allylic
sulfideylides:Li,J.;Ji,K.;Zheng,R.;Nelson, J.;Zhang, L.Chem. Commun.
2014, 50, 4130−4133.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: prabhu@orgchem.iisc.ernet.in.
ORCID
(16) Wang, Y.; Muratore, M. E.; Echavarren, A. M. Chem. - Eur. J. 2015,
21, 7332−7339.
Santhosh Rao: 0000-0003-1585-8803
Kandikere Ramaiah Prabhu: 0000-0002-8342-1534
Notes
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J. Beilstein J. Org. Chem. 2011, 7, 631−637. (b) Wang, J.; Yao, X.; Wang,
T.; Han, J.; Zhang, J.; Zhang, X.; Wang, P.; Zhang, Z. Org. Lett. 2015, 17,
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(18) Basavaiah, D.; Sreenivasulu, B. Tetrahedron Lett. 2002, 43, 2987−
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Chem. 2014, 53, 9907−9916. (b) Celik, M. A.; Dash, C.; Adiraju, V. A. K.;
Das, A.; Yousufuddin, M.; Frenking, G.; Dias, H. V. R. Inorg. Chem. 2013,
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(22) For selected reports showing the utility of the present [2,3]-
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by SERB (NO.SB/S1/OC-56/2013),
New Delhi, CSIR (No. 02(0226)15/EMR-II), and the Indian
Institute of Science. S.R. thanks UGC, New Delhi, for a
fellowship.
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