Phosphite-Catalyzed C?H Allylation of Azaarenes via an Enantioselective [2,3]-Aza-Wittig Rearrangement

Article abstract of DOI:10.1002/anie.201906681

A phosphite-mediated [2,3]-aza-Wittig rearrangement has been developed for the regio- and enantioselective allylic alkylation of six-membered heteroaromatic compounds (azaarenes). The nucleophilic phosphite adducts of N-allyl salts undergo a stereoselective base-mediated aza-Wittig rearrangement and dissociation of the chiral phosphite for overall C?H functionalization of azaarenes. This method provides efficient access to tertiary and quaternary chiral centers in isoquinoline, quinoline, and pyridine systems, tolerating a broad variety of substituents on both the allyl part and azaarenes. Catalysis with chiral phosphites is also demonstrated with synthetically useful yields and enantioselectivities.

Full text of DOI:10.1002/anie.201906681

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Accepted Article
Title: Phosphite Catalyzed C–H Allylation of Azaarenes via an
Enantioselective [2,3]-Aza-Wittig Rearrangement
Authors: Abdul Motaleb, Soniya Rani, Tamal Das, Rajesh G Gonnade,
and Pradip Maity
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Phosphite Catalyzed C–H Allylation of Azaarenes via an
Enantioselective [2,3]-Aza-Wittig Rearrangement
Abdul Motaleb,† Soniya Rani,† Tamal Das, Rajesh G. Gonnade and Pradip Maity*
Abstract: A phosphite mediated [2,3]-aza-Wittig rearrangement has
been developed for the regio- and enantioselective allylic alkylation
of six-membered hetero-aromatic compounds (azaarenes). The
nucleophilic phosphite adduct of N-allyl salts undergoes
a
stereoselective base mediated aza-Wittig rearrangement and
dissociation of the chiral phosphite for overall C–H functionalization
of azaarenes. This method provides efficient access to tertiary and
quaternary chiral centers in isoquinoline, quinoline, and pyridine
systems, tolerating a broad variety of substituents on both allyl part
and azaarenes. Catalysis with chiral phosphites is also
demonstrated with synthetically useful yields and enantioselectivities.
Chiral six-membered azaarenes, such as pyridines, quinolines,
and isoquinolines are among the most ubiquitous structural
motifs in pharmaceutical drugs, bioactive natural products, and
chiral ligands in asymmetric synthesis (Figure 1a).[1]
Consequently, great advances have been made in their
enantioselective synthesis.[2] For example, methods have been
developed that commence from acyclic precursors or pre-
functionalized azaarene halides and organometallic reagents.[2,3]
Recently, elegant protocols for the direct C–H alkylation from
feedstock azaarenes have also been reported.[4-6] Unfortunately,
an enantioselective C–H allylation of azaarenes has remained
elusive, despite the potential utility of the synthetically versatile
chiral allylated azaarene products for further functionalization
(Figure 1b).
In this Communication, we report the first enantioselective
C–H allylation of azaarenes via a conceptually novel chiral
phosphite promoted [2,3]-aza-Wittig rearrangement (Figure
1c). Our interest in enantioselective C–H functionalization of
imines embedded in azaarenes prompted us to explore the
possibility of umpolung reactivity.[7,8] We hypothesized that
Figure 1. Chiral azaarenes via a novel enantioselective C-H allylation. [a]
Chiral azaarene containing natural products. [b] Challenge in direct C-H
allylation. [c] Proposed phosphite catalyzed protocol with N-allyl salts.
N-allyl isoquinoline 1a was selected as the substrate for the
initial development of the stereoselective C–H allylation of
azaarenes (Table 1). As a proof of concept, stoichiometric
achiral dimethylphosphite (2a) was examined to test the
feasibility of the proposed reaction manifold. Addition of pre-
formed phosphite anion to 1a in the absence of light and oxygen
led to adduct 3,[10] which yielded 58% of the rearranged product
6a upon treatment with LiHMDS (entry 1). Next, we performed
the reaction with chiral TADDOL based phosphite 2b.[11]
Catalytic amounts (20 mol%) of 2b led to the formation of the
desired product in low yield, although with encouraging
enantioselectivity (78% ee, entry 2). The low yield in the range of
catalyst loading prompted us to carefully examine each step of
the proposed phosphite mediated cycle. Background reaction in
the absence of phosphite showed that in addition to
deprotonating intermediate 3, the base can also decompose 1a
(entry 3). Therefore we planned for slow addition of base to
maintain its concentration below intermediate 3. At -40 °C, the
rate of formation of 3 was studied with a varying stoichiometry of
1a (see SI) to determine the base addition rate during the course
of its consumption. Under slow base addition via syringe pump,
the product 6a yield increased to 28%, along with 32% N-allyl
isoquinolone 7a (entry 4). We believe the longer reaction time
required for the slow first step of the catalytic process (Figure 1c,
the phosphite-azaarene adduct
3 of N-allyl pyridinium 1
would undergo a base-mediated stereoselective aza-Wittig
rearrangement, in which the chiral phosphite would dictate
the stereochemical outcome of the reaction. Subsequent
elimination of the chiral phosphite from rearranged product
5
would reestablish aromaticity in the final product (6). We
further anticipated that the energy gain in rearomatization
might compensate for an otherwise less-favored aza-Wittig
rearrangement (Figure 1c).[9]
A. Motaleb, S. Rani, T. Das, Dr. R. G. Gonnade, Dr. P. Maity
Organic Chemistry Division, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune-411008, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-
201002, India
E-mail: p.maity@ncl.res.in
[†] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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Step 1, 1 to 3) led to the unavoidable incorporation of aerobic
for another reaction, which led to the formation of the desired
product with the same efficiency (entry 7). We opted to use the
stoichiometric phosphite method because of its easy operation,
shorter reaction time, and practicality. In addition, the chiral
phosphite was recovered and recycled.
Guided by previous reports of the counter cation effect on
stereoselective anionic [2,3]-Wittig rearrangements,[13] we carried
out a systematic screening of counter cations of the base. The
oxygen during base addition. As a result, substantial oxidation of
intermediate
4
occurred to form by-product 7a.[12] Since
carbanion 4 is the only oxidation prone intermediate, we tested
the base addition portion-wise instead to generate and
rearrange 4 in a discrete manner. Simple argon purging for 5
minutes before each portion-wise base addition led to 68%
rearrangement product with <5% oxidation (entry 5). Although
we could obtain near oxygen free rearrangement conditions,
use of KHMDS led to
a significant drop in yield and
moisture incorporation remained
a
problem, generating
enantioselectivity (entry 8). Base strength also impacted the
efficiency of the reaction, with stronger bases such as LDA and
n-BuLi leading to significant drops in both yields and
enantioselection (entries 9-10). After screening several solvents,
we identified THF as the optimal reaction medium. Other
solvents resulted in diminished yields and/or enantioselectivities.
We screened additional chiral phosphites to improve the
enantioselectivity of the reaction (see Supporting Information for
a complete optimization). Gratifyingly, in the presence of
phosphite 2k, the desired C–H allylation product 6a was
generated in 81% yield and 92% ee (entry 11).
hydroxide base upon reaction with LiHMDS. The hydroxide also
decomposes the starting material 1a slowly under the reaction
condition, leading to moderate yields.
The phosphite 2b was easily recovered during silica column
purification of the product. Hence, we tested the use of a
stoichiometric amount of 2b to form 3 at 0 °C, with subsequent
cooling and single base addition (<5 min) for the formation of the
desired product 6a. High yield was obtained (entry 6) in shorter
reaction time, and importantly, >95% of the chiral phosphite was
recovered after column chromatography. The chiral phosphite
that was recovered from column chromatography was recycled
Table 1. Optimization of aza-Wittig rearrangement via umpolung of N-allyl isoquinolinium salt
entry
1
2 (mol%)
2a (120)
2b (20)
-
T1 (°C), h1 (h)
0, 24
T2 (°C), h2 (h)
0, 1
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
base
6a yield (%)
6a ee (%)
7a yield (%)
ND
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
KHMDS
LDA
58
19
0
–
2
3a
0, 4
0, 1
78
ND
86
86
89
89
15
71
60
92
ND
0, 4
0, 1
ND
4
2b (20)
2b (20)
2b (100)
2b (100)
2b (100)
2b (100)
2b (100)
2k (100)
-40, 4
-40, 4
0, 48
-40, 92
-40, 92
-60, 2
-60, 2
0, 2
28
68
79
78
15
46
35
81
32
5b,c
6
7d
<5
ND
0, 48
ND
8
0, 48
ND
9
0, 48
0, 2
ND
10
11
0, 48
0, 2
n-BuLi
ND
0, 48
-60, 2
LiHMDS
ND
Reactions were carried out on 0.3 mmol scales. a1a completely decomposed. bportion-wise base addition; cwith 1.5 mmol 1a; dwith recovered phosphite 2b.
A diverse range of azaarene substrates were examined under
stoichiometric phosphite mediated method to determine the
scope of chiral phosphite mediated C–H allylation (Table 2).
Catalytic variants were tested for each class of azaarene, and
the results are presented in parenthesis. For substituted
isoquinolines, the reaction was tolerant of 3-bromo substitution
(6b), but the formation of the 3-phenyl isoquinoline product (6c)
was sluggish at –60 °C with a lower yield (~10%). An increase in
the reaction temperature to –40 °C resulted in the formation of
the desired product at a faster rate (4h), resulting in greater yield
(67%) and negligible loss in enantioselectivity (90% vs. 91% ee).
Isoquinoline substrates with 4-bromo, alkynyl, and phenyl
substitution all rearranged at –60 °C with similar efficiencies (6d-
f). Other functionalized phenyl rings at the isoquinoline C–4
position, including 4-chlorophenyl (6g), 4-fluorophenyl (6h), 3-
trifluoromethylphenyl (6i), and 2-bromophenyl (6j) were well
tolerated. A C–4 cyclopropyl group (6k) was also tolerated, as
the product was generated in 65% yield and 94%
enantioselectivity. 6-Bromo-substitution on the isoquinoline
resulted in 6l with good yield and higher enantioselectivity (96%
ee).
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Next, we varied the substitution in the allyl fragment of the
substrate. Other primary alkyl groups such as ethylphenyl (6m)
and TBS-protected hydroxymethyl (6n) worked well with no
significant effects on yields and enantioselectivities. The
sterically congested intermediate (3) of phosphite 2k. A relatively
smaller phosphite 2b resulted in the product 6q in 35% yield and
71% ee.
A terminal di-substituted geranyl substrate was examined next
to generate an all carbon quaternary stereogenic center. The
non-enantioselective version of the rearrangement went
uneventful with dimethylphosphite, but it failed to form the
product with the chiral phosphite (2k).[14] To our delight, a
smaller lithium pyrrolidinide base produced the desired product
(6r) in moderate yield (59%) but with high enantioselectivity
(90% ee). N-Geranyl salt of 4-phenyl isoquinoline was also
rearranged smoothly to give 6s in high enantioselectivity.
substrate with
substitution also
a
sterically bulky secondary cyclohexyl
rearranged successfully in good
enantioselectivity (6o). A six-membered C1–C2 endocyclic allyl
ring led to the formation of an exocyclic terminal alkene without
any alkene isomerization (6p).
The reaction with a cinnamyl moiety led to no product
formation. We suspect that the benzylic C–H of the product was
rendered more acidic with phenyl substitution, and LiHMDS
might deprotonate the product faster than deprotonation of
Table 2. Substrate scope for phosphite mediated (and catalyzed) asymmetric allylation of azaarenes
Conditions: Stoichiometric reaction conditions: THF solution of 1 (0.3 mmol) was added to 2 (0.3 mmol) and LiHMDS (0.3 mmol) in THF (0.1 M) at 0 °C, followed
by further addition of LiHMDS (2 equiv, 1 M in THF) at -60 °C for 2 h. Catalytic reaction conditions: 1 (1.5 mmol) and 2k (0.3 mmol) in THF (12 ml) at –40 °C,
followed by portiowise base addition over 90 h. Results of catalytic reactions are given in parenthesis. arearrangement step at –40 °C; b35% with 2b and no
product with 2k; clithium pyrrolidinide base instead of LiHMDS; dfirst step for 96 h.
Since most of the asymmetric azaarene functionalization
reports are specific to a particular type of azaarene,[3c,6] we
eagerly examined our method with other N-heteroaromatic
scaffolds. Gratifyingly, N-allyl quinolinium salt rearranged under
the same optimized reaction conditions to generate the
regioselective 2-allylated product (6t) in good yields but with
slightly lower enantioselectivity (77% ee) compared to its
isoquinoline counterpart (6a). 4-Phenyl (6u), 6-methyl (6v) and
6-bromo (6w) substituted quinoline led to slightly better
enantioselectivities (80-83% ee), whereas acridine as azaarene
(6aa) and cyclohexyl substitution on allyl (6z) resulted in the
enantioselectivity of the product comparable to the isoquinoline
level (90, 91% ee). On the other hand, 8-methoxy on quinoline
(6x) and TBS protected hydroxymethyl substitution on the allyl
part (6y) had a detrimental effect on enantioselectivity (66, 71%
ee).
Unsubstituted pyridine substrate failed to furnish any
rearrangement, but 2-phenyl pyridine led to 6ac in 54% yield
and 83% ee. Phenyl and 4-chlorophenyl substitution at C4 of
pyridine resulted in the formation of the rearrangement product
with dimethylphosphite and LiHMDS base, but chiral phosphite
(2k) promoted rearrangement failed.[14] Reaction with lithium
pyrrolidinide affected the rearrangements to moderate yields and
enantioselectivities (Table 2, 6ad and 6ae).
The lower enantioselection for most of the quinoline and
pyridine substrates prompted us to look into the possible effect
of alkene geometry. Unlike [3,3]-rearrangements that proceed
through well-ordered 6-membered transition states, the
stereoselectivity of [2,3]-rearrangements is often less predictable
and influenced by the nature and size of substituents,
presumably because of the conformationally more flexible 5-
membered transition states.[12a,15,16] Hence, we synthesized cis-
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allyl salts of quinoline (cis-1t), isoquinoline (cis-1a) and pyridine
(cis-1ad and cis-1ae) substrates. The cis-1a with catalyst 2k
produced the same enantiomer of 6a, albeit with slightly reduced
enantioselectivity (81 vs. 92% ee). On the other hand, the cis-
salts of quinoline and pyridine resulted in higher
enantioselectivities in the product than the trans-salts (Scheme
1). The higher enantioselectivity of cis-allyl quinoline and
pyridine salts indicates the possibility that other quinoline and
pyridine substrates may result in better enantioselectivity with
the corresponding cis-salts. We propose that the quinoline and
pyridine cis-substrates may have more pronounced energetic
differences in the competing transition states that lead to
stereoselective rearrangement products.[17] Interestingly, for all
three classes of azaarenes, both cis- and trans-substrates
furnished the same major enantiomer of the allylation product,
which suggests that the chiral phosphite dictates the
stereochemical outcome of the rearrangement of intermediate 4
to 5.
Scheme 1. Effect of alkene geometry on enantioselectivity of different
azaarenes.
Subsequent mechanistic studies were carried out to gain
support for the proposed aza-Wittig-rearomatization sequence
and shed light on the enantio-differentiating step (Scheme 2). A
crossover experiment with 1d and 1n furnished only the
respective intramolecular products with no cross products, which
indicates the rearrangement (Step 3) to be unimolecular
(Scheme 2a). The absence of competitive linear [1,2]-allyl
product is also suggestive of a concerted mechanism, consistent
with pericyclic Wittig rearrangements.[13b,18]
Scheme 2. Mechanistic studies. [a] Crossover experiment; [b] Enantio-
determining step; [c] Reactivity of non-aromatic substrates.
We also examined our hypothesis that regaining aromaticity to
obtain product
6
could be the driving force for this
unprecedented aza-Wittig rearrangement.[20] Dihydroisoquinoline
salts (8a, 8b) failed to rearrange up to room temperature,
presumably because of their inability to regain aromatic
stabilization. Instead, we observed partial oxidation to the lactam
(10a, 10b) over a prolonged reaction time (Scheme 2c). The
generation of lactam is suggestive of the formation of
carbanionic Wittig precursor 9 that reacts with aerobic oxygen,
similar to the isoquinoline derived intermediate.[12]
We were also interested in examining the enantio-determining
step of the reaction.[13b,16b] To gain insight, we examined the
configuration of the phosphite-azaarene adduct 3 and its
1
influence on the enantioselectivity. The H-NMR of intermediate
3 with phosphite 2b showed poor diastereoselectivity for the
newly formed carbon stereocenter, which did not correlate with
the high enantioselectivity observed for the overall reaction.[19]
Formation of intermediate 3 at different temperatures led to
different diastereomeric ratios, which had no influence on the
product enantioselectivity (Scheme 2b). These results indicate
that the initial ratio of diastereomers of carbanion 4 is irrelevant,
and that conversion of 4 to 5 involves a dynamic kinetic
resolution process whereby one diastereomer of 4 undergoes
[2,3]-rearrangement much faster than the other, while the
diastereomers of 4 readily interconvert.
In conclusion, we have developed a new approach for
asymmetric allylation of azaarenes via a phosphite promoted
tandem
aza-Wittig-rearomatization
sequence.
Careful
examination of reaction conditions revealed crucial roles of
solvent, counterion, base strength, and alkene geometry on the
stereoselectivity. Chiral azaarenes are furnished in good yields
and enantioselectivities with a broad range of functional groups.
Recovery of the chiral phosphite was almost quantitative and
shown to be active for reuse. The method is general for
isoquinoline, quinoline, and pyridine; and for the formation of
tertiary and all carbon quaternary centers. The evidence for
rearomatization as
a driving force for the reaction was
demonstrated. We are currently exploring this new mode of
activation for the development of other stereoselective reactions.
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See Supporting Information (SI) for general procedures and all
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This research was supported by the SERB (EMR/2015/000711)
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Keywords: Azaarene C–H allylation • Asymmetric
organocatalysis • Aza-Wittig rearrangement • Rearomatization •
TADDOL phosphite
−
,
−
−
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10.1002/anie.201906681
Angewandte Chemie International Edition
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Abdul Motaleb,† Soniya Rani,† Tamal Das,
Rajesh G. Gonnade and Pradip Maity*
Page No. – Page No.
Phosphite Catalyzed C–H Allylation of
Azaarenes via an Enantioselective [2,3]-
Aza-Wittig Rearrangement
Organocatalyzed enantioselective C–H Allylation of Azaarenes: A nucleophile phosphite
catalysis is introduced for overall C–H allylation of azaarenes via an facile aza-[2,3] Wittig
rearrangement sequence. TADDOL based phosphites induces high enentioselectivity.
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