A removable functional group strategy for regiodivergent Wittig rearrangement products

Article abstract of DOI:10.1039/c8ob02221f

[1,2] and [2,3] Wittig rearrangements are competing reaction pathways, often leading to uncontrollable product distribution. We employ a single removable functional group to fulfill the dual role of attaining a reversible [2,3] and stabilizing radical int

Full text of DOI:10.1039/c8ob02221f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
A removable functional group strategy for
regiodivergent Wittig rearrangement products†
Cite this: Org. Biomol. Chem., 2018,
16, 8922
Md Nirshad Alam,a,b Lakshmi K. M.a and Pradip Maity
*
a
Received 8th September 2018,
Accepted 2nd November 2018
DOI: 10.1039/c8ob02221f
rsc.li/obc
[1,2] and [2,3] Wittig rearrangements are competing reaction path- attainable, and stabilize the radicals I1/I2 for [1,2] products to
ways, often leading to uncontrollable product distribution. We be the next energetically achievable intermediates.
employ a single removable functional group to fulfill the dual role
An electron withdrawing FG would stabilize the carbanion
of attaining a reversible [2,3] and stabilizing radical intermediate (1−) to make it less reactive for all possible side reaction paths
for the [1,2] path to obtain both the Wittig products selectively for including [1,2] to offer a better chance for [2,3] product for-
a broad range of substrates.
mation selectivity under kinetic conditions. The stability could
also make the reversible [2,3] attainable via reducing its energy
gap with the oxo-anion product (2).6 But the carbanion substi-
tution influence on radical intermediates for the [1,2] path is
largely unknown.7 EWGs such as ester, amide, 2-oxindole,
ketone, and diester with stable carbanions are known to
produce only [2,3] products, even at a higher temperature (up
to 60 °C).2c,d,8 We suspect that the lack of [1,2] product for-
mation might be due to the unattainable [1,2] path rather than
the reversibility of [2,3]. A removable FG capable of dual anion
and radical stabilization seems to be the requirement to
achieve regiodivergency.
The base induced Wittig rearrangements of α-allyloxy carba-
nions (1−) are powerful carbon–carbon bond forming reactions
but often suffer from the requirement of a strong base and
competing [1,2] and [2,3] pathways.1 Other side reactions such
as β-elimination, [3,3] rearrangement, [1,4] shifts, and cycliza-
tion have also been reported.2 The product distribution
depends on the substrate nature, namely substitutions on
alkene and carbanion carbons.3 Only limited control over the
[2,3] product distribution is realized via varying the reaction
temperature.2d,4 Despite the [1,2] product being thermo-
dynamically stable and the [2,3] product being considered as
kinetically stable, a classical switch via controlling reversible
pericyclic [2,3] has not been achieved. The lack of generality
and control over product formation restricts the widespread
application of these useful classes of transformations (Fig. 1a).
A selective product formation of choice would allow both the
rearrangements to attain full synthetic utility.5
We started with 1,3-diheteroaromatic FGs (azoles), antici-
pating that they would stabilize both anions (1−) and radicals
We hypothesized that choosing a suitable removable func-
tional group (FG) on carbanion carbons could influence the
energy of both the intermediates (1− and I1/I2) appropriately,
and thereby control the reaction course for stereodivergency
(Fig. 1b). To achieve this, the FG effect on carbanions should
make the [2,3] path kinetic for all substitution types. For the
thermodynamic switch to [1,2], the FG influence on carbanion
(1−) should make the previously unexplored reversible [2,3]
aOrganic Chemistry Division, CSIR-National Chemical Laboratory, Pune-411008,
India. E-mail: p.maity@ncl.res.in
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02221f
Fig. 1 (a) Poor product selectivity for Wittig rearrangements. (b) A
single removable FG approach for regiodivergency.
8922 | Org. Biomol. Chem., 2018, 16, 8922–8926
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Communication
(I1/I2).9 Additionally, azoles are easy to remove from alcohol MeCN solvent led to the formation of mixtures of [2,3] and
products.10 Substrate classes 1A (R1 = Ar, R2 = H, R3 = Alk) and [1,2] products. Presuming that [2,3] is still the kinetic product,
1B (R1 = Ar, R2 = R3 = Alk) were selected to test the feasibility of we cooled the reaction mixture to −78 °C with a temperature
our hypothesis. KOtBu turned out to be an effective base in compatible solvent (THF) and base (n-BuLi). Gratifyingly, the
acetonitrile, and −40 °C reaction temperature led to fast and lower temperature resulted in only the [2,3] product in 88%
selective [2,3] product (2A-1,2,3 and 2B-2,3) formation yield and ∼1 : 1 dr (2C-1).3a The usual 0 °C reaction tempera-
(Scheme 1A).11 The reaction temperature was slowly increased ture with KOtBu as a base in MeCN solvent led to the selective
for 1A-1 having thiazole as the FG to obtain a possible regiodi- product switch (3C-1) in good yield (Table 1C). A variety of sub-
vergency via reversible [2,3] along with forward [1,2]. stituents on either aryl groups were well tolerated, with ortho-
Unfortunately, no change occurred prior to slow decompo- Me substitution resulting in high dr (9 : 1) for [2,3] products.
sition at 50 °C. Changing the FG to benzoxazole (1A-2) led to
Substrate class 1D with R1 = Ar and highly substituted
reversible [2,3],12 although no [1,2] product formed. But, to our alkene (R2 = Me, R3 = Ph) is known to be troublesome and
delight, substrate class 1B with benzoxazole (1B-2) results in a mostly avoided for Wittig rearrangements.2d Treatment of
successful product switch to [1,2] by raising the reaction temp- n-BuLi in THF or diethyl ether at low temperature, even up to
erature to 0 °C (3B-2, 78%). Benzothiazole as the FG turned −90 °C, resulted in only a [1,2] product (Table 1D & E). We
out to be the best FG with selective regiodivergent product for- replaced the removable FG with 2,3-dimethylthiazole (1D-2)
mation for both substrate classes (Scheme 1B). A complete which is the poorest for the [1,2] path with 1A-1. Still, substrate
product switch for 1A-3 occurred at room temperature, com- 1D-2 failed to produce any kinetic [2,3] product. Since we did
pared to that at 0 °C for 1B-3. The extra stabilization of the not obtain any [2,3] product, it is unclear if [2,3] is the kinetic
dialkyl allyl radical counterpart for the 1B substrate class pre- product or [1,2] became both the kinetic and thermodynamic
sumably lowers the overall activation energy requirement for product for the 1D substrate class.
[1,2]. It is worth noting that only the anion stabilizing ability
of the FG is not enough and both anion and radical stabiliz- with an alkyl group at the carbanion carbon (R1 = alkyl).
ation abilities enabled the regiodivergent reaction paths.13 KOtBu was found to be not strong enough, but KHMDS or
Next, we repeated the entire alkene substitution pattern
With the discovery of benzothiazole as a suitable FG for n-BuLi successfully deprotonated to form the carbanion. A
regiodivergency, we set to study all possible substrate classes benzothiazole FG enabled direct alkyl carbanion generation is
with varying substitution at every position. Other class 1A sub- significant since it is not feasible otherwise, due to the lower
strates with different aryl groups (R1) were tested successfully acidity of carbanion C–H compared to those of allylic protons.
(Table 1A). The product switch for both electron rich and poor As a result, rearrangements with carbanion carbon having
groups at the para-position is faster than that for the unsubsti- alkyl or no substitution were generally realized via a Stille–
tuted one, which indicates radical intermediacy for the [1,2] Wittig transmetalation pathway.15
path.14 The dr ratio of [2,3] products for 1A is low to moderate
(∼1 : 1 to 3.5 : 1).
As with substrate class 1D, the highly stable allyl radical in
1E-1 (R2 = Me, R3 = Ph) made the [1,2] path fast even at
Substrate class 1B with R2 = Ar and both R3 = R4 = Me gave −90 °C, with no detection of the [2,3] product (Table 1D & E).
[2,3] at −40 °C, and completely switched to the [1,2] product at
The complete product switch for mono-aryl (1F-1, 1F-2)
0 °C in 4 h reaction time (Table 1B). The yields for both the and dimethyl substituted alkene substrates (1G-1) were easily
regioisomeric products are good with unsubstituted phenyl attainable, with good yields for all [2,3] and [1,2] products
and differently substituted aryl groups such as 3-Br and 2-F.
Substrate class 1C with R2 = Ar, R3 = H, R4 = Ar was tested
(Table 1F & G).
The mono-alkyl substituted alkene 1H-1 (R2 = H, R3 = Alkyl)
next, where the reaction at −40 °C with KOtBu as a base in resulted in 86% yield for [2,3], but no product switch occurred
Scheme 1 Single removable functional group (FG) at carbanion carbon and its effect on Wittig rearrangements.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8922–8926 | 8923

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 1 Regiodivergent Wittig products with differently substituted alkenes and carbanion carbons
Conditions: 0.1–0.3 mmol 1, 2–3 equiv. base. a ∼22% unidentified isomer. b ∼15% [2,3] product remained along with ∼20% unidentified isomer.
c Side product formed in 60% yield. d FG = 4,5-dimethylthiazole. e FG = N-methylimidazole.
with slow decomposition at 50 °C (Table 1H). We expected the product provided it is still the kinetic one.16 Additionally, a tra-
[1,2] activation to be the highest with the least stable radical celess group would have the advantage of no extra chemical
pair combination. An extended naphthothiazole substrate step requirement for its removal. We synthesized a traceless
(1H-2) was prepared next to enhance the radical stability. Still, phosphonate FG version of 1D and a cyano version of 1E fol-
no [1,2] product formed at room temperature but the reaction lowing literature procedures.17 To our delight, both generated
at 50 °C led to slow formation of the [1,2] product in (3H-2) only a branched allyl ketone product18 via [2,3] rearrangement
poor yield (40%). The result with 1H-2 indicates a better followed by irreversible traceless group detachment
radical stabilizing FG, which would enable an efficient product (Scheme 2). The quaternary carbon in between the keto and
switch for this substrate class as well.
alkene made these products stable under the basic reaction
Overall, with benzothiazole as a removable FG, a large conditions. Overall, although the same FG did not produce
variety of substrate classes with different substitution patterns
yielded [2,3] and [1,2] products regiodivergently, simply via
controlling the reaction temperature. Substrate class 1H
resulted in poor yield for [1,2], while a highly substituted allyl
group in 1D and 1E led to no [2,3] product formation.
To obtain the unattainable [2,3] with the substrate classes
1D and 1E, we tried to find an FG capable of anion stabiliz-
ation but not radical stabilization. We planned to start with a
traceless FG having those properties, which would leave the
Scheme 2 A traceless FG to trap [2,3] rearrangement with a highly sub-
rearranged product quickly and irreversibly to trap the [2,3] stituted alkene.
8924 | Org. Biomol. Chem., 2018, 16, 8922–8926
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Communication
regiodivergency, the choice of two complementary FGs led to manipulation of intermediate stabilization for both reaction
the regioisomeric products of choice with a highly substituted paths. The strategy was applied to a broad range of substitu-
alkene.
ents at each position, and even with a propargylic system.
Intrigued by the success of different types of allylic Benzothiazole was removed in a single operation under mild
rearrangements, we explored a possible regiodivergent route conditions without isomerization of alkenes in a highly reac-
for a propargylic substrate as well. Propargyl substrates are tive allyl ketone. The challenging highly substituted alkene
known to generate only [1,2] products with a moderate yield, and substrates were successfully used with a traceless FG strategy
an allene via [2,3] is rare with very poor yield.19 We synthesized for selective [2,3] product formation. Currently, we are explor-
1I-1 with a phenyl substituted alkyne, and upon treatment with ing the possibility of making these rearrangements catalyti-
KOtBu, it resulted in an allene via [2,3] at −40 °C. The starting cally enantioselective, using the coordination and anion stabi-
ether completely transformed to a [1,2] product in 52% yield lization power of the removable functional groups.
upon warming to room temperature (3I-1) (Scheme 3).
The emergence of benzothiazole as the common removable
FG for all substrate classes allowed a single removal method to Conflicts of interest
be sufficient. We chose 2C-1 as the model since [2,3] products
are sterically more demanding, and the aryl, allyl ketone
There are no conflicts to declare.
product (4C-1) would be the most challenging one due to its
propensity for isomerization. Quaternization of benzothiazole
with MeOTf in the presence of a weak and insoluble base
Acknowledgements
K2CO3 in diethyl ether led to the formation of FG-detached
The authors gratefully acknowledge the financial support from
the SERB (EMR/2015/000711) and the CSIR-NCL (MLP030926).
Md N. A. thanks the UGC for a fellowship.
allyl ketone product 4C-1, with very little alkene isomerization
(Scheme 4).8,16 The α-hydroxy benzothiazole unit is also well
utilized in the literature for one carbon homologated
α-hydroxy carbonyl compounds.20
In conclusion, a single removable FG was successfully uti-
lized for the synthesis of regiodivergent Wittig products. The
Notes and references
attachment of benzo-thiazole allowed us to obtain a previously
unattainable reversible [2,3] Wittig and favorable [1,2] via
1 (a) T. Nakai and K. Mikami, Chem. Rev., 1986, 86, 885;
(b) K. Tomooka, H. Yamamoto and T. Nakai, Liebigs Ann./Recl.,
1997, 1275; (c) H. T. West, M. S. S. Spoehrle, K. Kasten,
E. J. Taylor and A. D. Smith, ACS Catal., 2015, 5, 7446.
2 (a) U. Schollkopf, Angew. Chem., Int. Ed. Engl., 1970, 9, 763;
(b) V. M. Leonova, R. M. Baimuratov and N. Y. Klimochkin,
Russ. J. Org. Chem., 2014, 50, 1268; (c) E. S. Denmark and
R. L. Cullen, J. Org. Chem., 2015, 80, 11818;
(d) R. C. Kennedy, A. J. Guidera and N. E. Jaconsen, ACS
Cent. Sci., 2016, 2, 416; (e) M. L. Mori-Quiroz Jr. and
R. E. Maleczka, J. Org. Chem., 2015, 80, 1163;
(f) R. E. Maleczka Jr. and F. Geng, Org. Lett., 1999, 1, 1115;
(g) K. Gilmore, M. Manoharan, C. I. J. Wu, R. V. P. Schleyer
and V. I. Alabugin, J. Am. Chem. Soc., 2012, 134, 10584.
3 (a) M. Tsubuki, T. Kamata, H. Okita, M. Arai, A. Shigihara and
T. Honda, Chem. Commun., 1999, 2263; (b) K. Tomoka,
H. Yamamoto and T. Nakai, J. Am. Chem. Soc., 1996, 118, 3317.
4 (a) Y. Yamamoto, J. Oda and Y. Inouye, Tetrahedron Lett.,
1979, 26, 2411; (b) J. Cast, S. T. Stevens and J. Holmes,
J. Chem. Soc., 1960, 3521.
Scheme 3 Single removable FG mediated regiodivergent Wittig reac-
tion with propargyl ether.
5 For a review on catalyst controlled regiodivegent reactions,
see: N. Funken, Q. Y. Zhang and A. Gansuer, Chem. – Eur.
J., 2017, 23, 19.
6 Although a reversible [2,3] Wittig reaction is not known, a
double heteroatom reversible reaction is known, presum-
ably due to less energy differences: (a) S. G. Davies,
J. F. Fox, S. Jones, A. J. Price, M. A. Sanz, T. G. R. Sellers,
A. D. Smith and F. C. Teixeira, J. Chem. Soc., Perkin Trans. 1,
2002, 1757; (b) S. U. Pandya, C. Garçon, P. Y. Chavant, S. Py
and Y. Vallée, Chem. Commun., 2001, 1806. Regiodivergent
Scheme 4 FG removal for allyl ketones and one carbon added
alcohols.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8922–8926 | 8925

View Article Online
Communication
Organic & Biomolecular Chemistry
[2,3] and [1,2] Stevens rearrangements have been achieved 14 R. A. Benkeser, M. P. Siklosi and E. C. Mozdzen, J. Am.
recently: (a) B. Biswas, C. S. Collins and A. D. Singleton, Chem. Soc., 1978, 100, 2134.
J. Am. Chem. Soc., 2014, 136, 3740; B. Biswas and 15 Review on Stille–Wittig reactions: L. Rycek and T. Hudlicky,
A. D. Singleton, J. Am. Chem. Soc., 2015, 137, 14244; (b) B. Xu
and U. K. Tambar, J. Am. Chem. Soc., 2016, 138, 12073.
7 (a) W. C. Still, J. Am. Chem. Soc., 1978, 100, 1481;
(b) K. Tomooka, T. Igarsashi and T. Nakai, Tetrahedron,
Angew. Chem., Int. Ed., 2017, 56, 6022.
16 For the traceless FG strategy in the [2,3] Wittig rearrange-
ment: A. R. Katritzky, H. Wu and L. Xie, J. Org. Chem.,
1996, 61, 4035.
1995, 50, 5927; (c) R. Hoffmann, T. Riickert and 17 For 1D-4 synthesis: (a) Y. Zhou, Y. Zhang and J. Wang, Org.
R. Bruckner, Tetrahedron Lett., 1993, 34, 297.
8 Unpublished work. For captodative stability via push–pull
substitutions: H. Viehe, Z. D. Anousek and R. Merenyi, Acc.
Chem. Res., 1985, 18, 148.
Biomol. Chem., 2016, 14, 10444; (b) A. Kondoh and
M. Terada, Org. Lett., 2013, 15, 4568. For 1E-2 synthesis:
(a) B. Cazes and S. Julia, Synth. Commun., 1977, 7, 113–117;
(b) V. S. V. S. N. Swamy, M. K. Bisai, T. Das and S. S. Sen,
Chem. Commun., 2017, 53, 6910.
9 A. Dondoni and A. Marra, Chem. Rev., 2004, 104, 2557.
10 The reversible [2,3] was determined by the fact that the dia- 18 For reports on allyl ketone synthesis: (a) S. Omura,
stereomeric ratio of a low-temperature reaction changed to
a poor dr at room temperature.
11 L. Rycek and T. Hudlicky, Angew. Chem., Int. Ed., 2017, 56,
T. Fukuyama, J. Horiguchi, Y. Murakami and I. Ryu, J. Am.
Chem. Soc., 2008, 130, 14094; (b) F. Shibahara, J. F. Bower
and J. M. Krische, J. Am. Chem. Soc., 2008, 130, 14120;
(c) A. Q. Chen, F. A. Cruz and M. V. Dong, J. Am. Chem. Soc.,
2015, 137, 3157; (d) C. Samann and P. Knochel, Synthesis,
2013, 45, 1870.
6022.
12 F. Peng and S. J. Danishefsky, J. Am. Chem. Soc., 2012, 134,
18860.
13 For selective [2,3] with substituted carbanion carbons, 19 (a) A. J. Marshall, E. D. Robinson and A. Zapata,
please see: A. McNally, B. Evans and M. J. Gaunt,
J. Org. Chem., 1989, 54, 5854 and ref. 14.
Angew. Chem., Int. Ed., 2006, 45, 2116; and (2d).
20 A. Dondoni, Org. Biomol. Chem., 2010, 8, 3366.
8926 | Org. Biomol. Chem., 2018, 16, 8922–8926
This journal is © The Royal Society of Chemistry 2018