Iodo Meyer-Schuster rearrangement of 3-alkoxy-2-yn-1-ols for β-mono (exclusively Z-selective)-/disubstituted α-iodo-α,β-unsaturated esters

Article abstract of DOI:10.1021/ol502224s

We herein present the iodo Meyer-Schuster rearrangement of 3-alkoxypropargyl alcohols for α-iodo-α,β-unsaturated esters using iodine or NIS in dichloromethane at ambient temperature. Substrates prepared from both aldehydes and ketones are found to be equally good feedstock for the reaction to produce β-mono-and-disubstituted products. Irrespective of the substitution, substrates prepared from aldehydes gave Z-isomers exclusively. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502224s

Letter
pubs.acs.org/OrgLett
Iodo Meyer−Schuster Rearrangement of 3‑Alkoxy-2-yn-1-ols for
β‑Mono (Exclusively Z‑Selective)-/Disubstituted α‑Iodo-α,β-
Unsaturated Esters
Surendra Puri,† Nuligonda Thirupathi,† and Maddi Sridhar Reddy*,†,‡
†Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur
Road, P.O. Box 173, Lucknow 226031, India
‡Academy of Scientific and Innovative Research, New Delhi 110001, India
S
* Supporting Information
ABSTRACT: We herein present the iodo Meyer−Schuster rearrangement
of 3-alkoxypropargyl alcohols for α-iodo-α,β-unsaturated esters using iodine
or NIS in dichloromethane at ambient temperature. Substrates prepared
from both aldehydes and ketones are found to be equally good feedstock for
the reaction to produce β-mono- and -disubstituted products. Irrespective of
the substitution, substrates prepared from aldehydes gave Z-isomers
exclusively.
eyer−Schuster rearrangement offers an efficient approach
propargyl alcohols) was reported by Wang and Chen4 for the α-
iodo-α,β-unsaturated aldehydes, by using iodide (aqueous HI in
toluene) rather than an iodonium ion through a different
pathway of involving iodoallene intermediates and their oxygen-
mediated oxidation. The Meyer−Schuster rearrangement is yet
to be extended to the alkoxy propargyl alcohols for the synthesis
of α-iodo-conjugated esters which are valuable subunits for the
stereodefined entry to highly substituted olefins through
modification of the ester functional group and by the metal
catalyzed coupling reactions on the vinyl iodide unit. Filling this
gap, and as part of our ongoing program of unveiling the new
reactions of functionalized alkynes through electrophilic
activation,5 we herein report the synthesis of α-iodo-α,β-
unsaturated esters with both β-mono- and -disubstitution. This
was achieved using only I2 or NIS as reagents with the exclusion
of any assistance of metal catalysts, and under very mild
conditions.
M
for the construction of a variety of highly substituted (di-,
tri-, and tetra-) conjugated carbonyl compounds and α,β-
unsaturated esters.1,2 Given the catalytic nature of the reaction,
this has become a versatile alternative to the classical aldol
condensation and Wittig reaction while largely expanding the use
of readily available propargyl alcohols. A number of metal
systems along with several Bronsted acids have been identified
for the successful execution of these transformations. In the same
line, Zhang et al. reported (Scheme 1, eq 2) an iodo Meyer−
Scheme 1. Synthesis of α-Halo Conjugated Carbonyls
Although the synthesis of α-halo-conjugated esters through a
halogenated Wittig reaction and some other approaches are
reported in the literature,6 the protocols were mostly restricted to
aldehydes as substrates or for the bromoadducts. And the
outcome of the reactions often seriously suffered from the
formation of mixture of diastereomers, leaving its general
synthesis still a formidable challenge to synthetic chemists. The
method we present here is not only equally applicable for the
substrates from both aldehydes and ketones but also highly
stereoselective (Z-only) for the β-monosubstituted adducts.
Initially we selected a known substrate 1a7 for optimization
studies. With the experience of activating the ethoxy alkynes
using I2 without the assistance of any metal catalyst,5e we treated
1a with I2 in CH2Cl2 (Table 1, entry 1). Unfortunately, it
Schuster rearrangement3 through a novel concept for the general
synthesis of α-iodo-α,β-unsaturated carbonyl compounds where
an Au catalyst was needed for the alkyne activation followed by
Au−I exchange, a Mo catalyst for the hydroxyl migration, and a
phosphine catalyst to suppress the byproducts. Prior to that, a
similar transformation (with a restriction to aryl and terminal
Received: July 28, 2014
Published: September 26, 2014
© 2014 American Chemical Society
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Letter
Table 1. Optimization of Reaction Conditions
c
b
entry
substrate
reagent
base
solvent
temp/time (h)
product (ratio)
yield
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
5a
5a
I2
−
−
−
−
−
CH2Cl2
CH2Cl2
DCE
rt/0.5
0 °C/1.5
rt/0.5
rt/0.5
rt/0.5
rt/0.5
rt/0.5
rt/0.5
rt/1
2a + 3 (3:2)
2a + 3 (6:1)
2a + 3 (2.3:1)
2a + 3 (7:1)
2a + 3 (2:1)
2a + 3 (3:1)
2a + 3 (3:1)
2a (E/Z)
2a (E/Z)
2a (E/Z)
−
68%
62%
65%
58%
55%
60%
60%
59%
65%
63%
−
2
I2
3
I2
4
I2
THF
5
I2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
6
I2
NaHCO3
Na2CO3
K2CO3
−
−
TEA
7
I2
8
I2
9
NIS
NIS
I2
10
11
12
13
14
15
rt/1
CH2Cl2
CH2Cl2
toluene
CH2Cl2
rt/12
rt/12
rt/5
I2
Py
−
2a
−
I2
K2CO3
−
−
65%
75%
70%
I2
rt/5
6a
NIS
CH2Cl2
rt/10
c
6a
a
b
1
2 mmol of reagent were added to 1 mmol of substrate in solvent (0.25 M). Isolated yield. Ratio of the products was calculated from H NMR.
produced an inseparable mixture of required product 2a and
non-iodo Meyer−Schuster product 3. The fate of the reaction
did not change with the variation in temperature (0 °C, entry 2)
and solvent (DCE, THF or toluene, entries 3−5) or by the
addition of the base NaHCO3 or Na2CO3 (entries 6−7).
We reasoned that the high reactivity of ethoxyalkyne makes it
sensitive to the acidic nature of the reaction medium and as a
result led to proton assisted Meyer−Shuster rearrangement. Use
of K2CO3 with I2 (entry 8) or NIS in place of I2 (entries 9 and 10)
suppressed the formation of byproduct 3, but the required
product 2a was formed as an inseparable mixture of E/Z isomers.
Strangely, organic bases TEA and Py (entries 11 and 12)
produced an unidentified intermediate which slowly converted
to the product during the purification, making the approach
unreliable. Finally, to our pleasure, use of K2CO3 as a base with I2
in nonpolar solvent, toluene, cleanly afforded 2a as a single
isolable product in 65% yield.
With optimal reaction conditions (I2, CH2Cl2, rt) in hand, the
scope and limitations of this reaction were then investigated. As is
evident from Scheme 2, the iodo Meyer−Shuster rearrangement
was found to be quite effective over a wide range of phenoxy
alcohols. Similar to 5a, halo (Br, Cl, F) substituted substrates
5b−e afforded, upon exposure to I2 in CH2Cl2, the
corresponding products 6b−e in 70−85% yields. Substrates
Scheme 2. Iodo Meyer Schuster Rearrangement of Substrates
1 and 5 Prepared from Aldehydes
Meanwhile, we worked with phenoxy propargyl alcohol 5a
(prepared by the addition of phenoxy acetylide8 to benzalde-
hyde) instead of 1a for the following reasons: (1) the reactivity of
phenoxyalkyne is relatively less due to the sharing of oxygen’s
lone pair electrons between the alkyne and phenyl ring, and
hence it may not undergo undesired Meyer−Schuster rearrange-
ment; (2) the shelf life of 5 is very high compared to 2 which
slowly forms 3 on standing; (3) although commercially available,
ethoxyacetylene is expensive whereas phenoxy dichloroethene 4
(equivalent of phenoxy acetylene) can be synthesized in large
scale (more than 100 g) from cheaply available trichloroethene
and phenol.
Realizing our conception, the reaction of 5a with I2 occurred
very selectively at rt to afford the required product 6a as a sole
outcome in 75% yield while no undesired Meyer−Shuster
product (7) was detected (entry 14). Delightedly, 6a was found
to be formed exclusively as a Z-isomer (vide infra, Scheme 5).
NIS in CH2Cl2 also worked well for the transformation but with a
prolonged reaction time (entry 15, 70% 6a).
a
1 mmol of 1 or 5 in 4 mL of solvent (toluene for 1 and CH2Cl2 for 5)
was added to 2 mmol of I2 (and 2 equiv of K2CO3 in the case of 1) at
rt, and the contents were stirred until completion (TLC). Isolated
yields.
b
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5f−h with an electron-withdrawing nitro group also gave an
excellent outcome (6f−h in 75−80% yields) while their electron-
rich counterpart 5i resulted in moderate yield (65%) of the
product 6i. Pleasingly, heteroaryl substituted adducts 6j and 6k
were also obtained in good yields (66−73%) under the standard
conditions.
exclusively. While assisted by an acidic atmosphere created by
I2, the presence of an adjacent aliphatic proton to tertiary alcohol
tempted the substrate to take an alternative pathway of
elimination before allowing the expected iodo Meyer−Schuster
rearrangement. Use of a base also did not change the course of
the reaction.
We then switched to the alternative nonacidic reagent, NIS
(which was proved to be almost equally effective as is evident
from Table 1), for the transformation. Pleasingly, the expected
transformation of 8a to 10a occurred very smoothly (80%) with
2 equiv of NIS in CH2Cl2 at rt.
Remarkably, the reaction on alkyl substituted substrates 5l−n
also suffered neither selectivity issues producing exclusively Z-
isomers nor low conversion rates which was expected due to
relatively tough C−OH bond cleavage compared to that of
benzyl alcohol counterparts 5a−k. Thus, the products 6l−n were
obtained in 70−73% yields. The result indicated that the total Z-
selectivity is only because of steric hindrance and not due to
conjugation factors. Notably, skipped olefinic product 6o was
also smoothly obtained in 75% yield. Additionally, ethyl
counterparts (2a−f) of a few of the products were synthesized
from corresponding ethoxypropargyl alcohols (1a−f), in their
standardized conditions (I2, K2CO3, toluene, rt) to expand the
scope of the approach. The yields of the phenoxy conjugated
esters (6a−o, 65−85%) were higher than those of ethyl
conjugated esters (2a−f, 60−75%)
Similarly, substrates 8b−d, prepared from other cyclic ketones,
also underwent the title transformation to afford the
corresponding products (8b−d) in excellent yields (63−80%).
The sterically hindered substrates 8e and 8f, prepared from
adamantanone and dicyclohexyl ketone respectively, also
smoothly reacted under the optimized conditions to give the
corresponding products (10e and 10f) in 70−88% yields.
Further, substrates from acyclic ketones also were indiscrimin-
ately converted to the corresponding β-disubstituted conjugated
esters 10g−j in 60−90% yields. Of note is that the substrates with
less acidic 3°-H adjacent to the tert-hydroxyl group (8e−f, 8j, and
8l) were relatively more productive. Substrates from unsym-
metrical aliphatic ketones (8k−8l) afforded the mixture of
diastereomers with the ratio changing along with the steric bias.
Significantly, diphenyl substituted adduct 10m was obtained
from 8m in 58% yield, at relatively lower temperatures (0 °C−rt)
which was necessary to avoid some decomposition. Likewise,
halosubstituted diphenyl adducts 10n−o were also obtained,
without any obstruction, in moderate yields of 55−62%. Next,
mixed ketone (aryl-alkyl) based substrates 8p−r also reacted
smoothly and provided the corresponding products 10p−r, as a
diastereomeric mixture, in moderate yields of 60−65%.
Moving forward, we chose substrates prepared from ketones
which would give β-disubstituted adducts. Initially, when we
subjected the substrates 8a−c (Scheme 3), synthesized from
aliphatic ketones, to I2 in CH2Cl2 (rt or 0 °C), the eliminated
products 9a−c (respectively) were formed instantly and
Scheme 3. Iodo Meyer Schuster Rearrangement of Substrates
a
,b
8 Prepared from Ketones
A plausible mechanism for the title reaction is depicted in
Scheme 4. Accordingly, activation of electron-rich alkyne (A) by
Scheme 4. Proposed Mechanism
an electrophilic iodine reagent might lead to iodoketene
oxonium ion B which would instantly undergo intramolecular
hydroxyl attack to give four membered intermediate C. We
exclude concerted conversion of A to C reasoning that the
hydroxyl group and β-carbon of the alkyne are too long to react
unlike in the case of B in which the reactive centers fall in closer
proximity. The strained ring in C will then undergo slow cleavage
to deliver the thermodynamic (less sterically hindered Z-isomer)
product 2 or 6 or 10.
Next, we performed some reactions on products 6a, 6m, and
10m to prove the geometry of the product as well as to extend the
importance of the method to the stereodefined synthesis of
multiply substituted olefins (Scheme 5). Thus, the reduction of
6a and 6m with DIBAL-H in CH2Cl2 produced a known
conjugated compound 11a,9 providing proof for the Z-geometry
a
2 mmol of NIS were added to 1 mmol of 8 in 4 mL of CH2Cl2 at rt
(0 °C for 8m−o) and stirred the contents at rt. b Isolated yields. c The
ratio was determined by H NMR.
1
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Scheme 5. Utilizations of Functional Groups of α-Iodo
Conjugated Ester 6 or 10
of the substrate, and the unknown nonconjugated 11b. The
NOESY spectroscopy of both 11a and 11b supported the Z-
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literature and spectral data comparison unambiguously estab-
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methylenedioxy phenyl boronic acid 12 in the presence of
catalytic Pd(0) and 2 equiv of Cs2CO3 produced 13 in 59% yield
whereas Sonogashira coupling of 6a and 10m with phenyl-
acetylene with the assistance of catalytic Pd(II) yielded
trisubstituted olefin 14a and tetrasubstituted olefin 14b
respectively in 55−66% yields.
In summary, an efficient synthesis of linear α-iodo-α,β-
unsaturated esters from readily accessible propargylic alcohols is
described. This reaction works well not only with substrates
derived from aldehydes but also with those from ketones to
produce a highly substituted olefin center. Z-isomers were
exclusively obtained in the case of substrates prepared from
aldehydes. Some functional group transformations are per-
formed on few of the products to offer a stereodefined entry to
selective tri- and tetrasubstituted olefins.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and copies of H and 13C spectra for
1
compounds 2a−f, 5a−o, 6a−o, 8a−r, 9a−b, 10a−r, 11a−b, 13,
and 14a−b. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(9) Hashmi, A. S. K.; Haffner, T.; Rudolph, M.; Rominger, F. Eur. J.
Org. Chem. 2011, 667−671.
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Org. Biomol. Chem. 2013, 11, 8065−8072. (b) Moreau, X.; Campagne,
J.-M. J. Org. Chem. 2003, 68, 5346−5350. (c) Roy, S.; Anoop, A.;
Biradha, K.; Basak, A. Angew. Chem., Int. Ed. 2011, 50, 8316−8319.
(d) Karama, S. Synth. Commun. 2010, 40, 3447−3451.
*E-mail: msreddy@cdri.res.in; sridharreddymaddi@yahoo.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.P. and N.T. thank CSIR for the fellowships. We thank SAIF
division CSIR-CDRI for the analytical support. We gratefully
acknowledge the financial support by CSIR-Network project
‘BSC0104’ (CSIR-CDRI-SPLenDID) and by DST under ‘Fast
Track Proposal Scheme for Young Scientists’ (Project No. SB/
FT/CS-102/2012). CDRI Communication No. 8800.
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