Yttrium-Catalyzed Intramolecular Hydroalkoxylation/Claisen Rearrangement Sequence: Efficient Synthesis of Medium-Sized Lactams

Article abstract of DOI:10.1002/anie.201700596

An efficient yttrium-catalyzed intramolecular hydroalkoxylation/Claisen rearrangement sequence has been achieved, thus enabling facile access to a diverse array of valuable medium-sized lactams. Furthermore, a mechanistic rationale for this novel cascade

Full text of DOI:10.1002/anie.201700596

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700596
German Edition: DOI: 10.1002/ange.201700596
Heterocycles
Yttrium-Catalyzed Intramolecular Hydroalkoxylation/Claisen
Rearrangement Sequence: Efficient Synthesis of Medium-Sized
Lactams
Bo Zhou, Long Li, Xin-Qi Zhu, Juan-Zhu Yan, Yi-Lin Guo, and Long-Wu Ye*
Abstract: An efficient yttrium-catalyzed intramolecular
hydroalkoxylation/Claisen rearrangement sequence has been
achieved, thus enabling facile access to a diverse array of
valuable medium-sized lactams. Furthermore, a mechanistic
rationale for this novel cascade reaction is well supported by
a variety of control experiments.
Recently, transition-metal-catalyzed tandem intramolec-
ular alkoxylation/Claisen rearrangement has attracted con-
siderable interest in organic synthesis because of its high
bond-forming efficiency and atom economy in the formation
of functionalized cyclic compounds.[6–9] For example, gold- or
platinum-catalyzed domino reactions involving alkoxylation
and subsequent Claisen-type rearrangement for the prepara-
tion of five- and six-membered heterocycles has been well
established by the groups of Hashmi, Liu, and others
(Scheme 1a).[7] In a related study, Rhee et al. reported an
M
edium-sized lactams (8- to 11-membered rings), espe-
cially the eight-membered lactams (benzazocinones), are
important structural motifs which have been found in
bioactive molecules and natural products (Figure 1).[1] How-
Figure 1. Benzazocinones in bioactive molecules and natural products.
ever, such units are regarded as difficult structures to access
because of entropic effects and transannular interactions,[2]
and only very limited methods have been developed to
date,[3–5] with intramolecular carbonylation[3] and ring-closing
metathesis (RCM)[1e,4] being the most popular choices. Thus,
new methods for the efficient construction of this type of
skeleton are highly desired.
Scheme 1. Transition-metal-catalyzed tandem intramolecular alkoxyla-
tion/[3,3] rearrangement. PG=protecting group.
[*] B. Zhou, L. Li, X.-Q. Zhu, J.-Z. Yan, Y.-L. Guo, Prof. Dr. L.-W. Ye
Collaborative Innovation Center of Chemistry for Energy Material,
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory for Chemical Biology of Fujian Province and College of
Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (China)
elegant protocol for the synthesis of various cycloheptane
skeletons by gold-catalyzed alkoxylation of 3-alkoxy-1,6-
enynes/Claisen rearrangement (Scheme 1b).[8a] In 2015,
Toste et al. disclosed its enantioselective version by asym-
metric desymmetrization strategy (Scheme 1c).[8b] Despite
these remarkable achievements, these intramolecular cascade
reactions have so far been limited to noble-metal catalysts. In
addition, the construction of important medium-sized rings by
this strategy has not been reported to date. Inspired by our
recent study on ynamide chemistry,[10,11] we envisioned that
E-mail: longwuye@xmu.edu.cn
Prof. Dr. L.-W. Ye
State Key Laboratory of Organometallic Chemistry, Shanghai Insti-
tute of Organic Chemistry, Chinese Academy of Sciences
Shanghai 200032 (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700596.
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Table 2: Reaction scope for the formation of the benzazocinones 2.[a]
the synthesis of eight-membered benzolactams (2) might be
achieved by catalytic intramolecular hydroalkoxylation of
ynamides (1) and subsequent Claisen rearrangement. Herein,
we describe the realization of such an yttrium-catalyzed
tandem intramolecular hydroalkoxylation/Claisen rearrange-
ment, thus allowing the atom-economical synthesis of various
synthetically useful benzazocinones (Scheme 1d). In addi-
tion, this chemistry can be extended to the direct construction
of other types of valuable medium-sized lactams. Moreover,
the mechanistic rationale for this novel tandem sequence is
well supported by a variety of control experiments.
Table 1 shows the realization of the cascade cyclization of
the ynamide 1a in the presence of various transition metals.[13]
To our delight, typical gold catalysts such as IPrAuNTf2 and
Table 1: Optimization of reaction conditions.[a]
Entry
Catalyst
Reaction conditions
Yield [%][b]
2a
2aa
1
2
3
4
5
6
7
8
IPrAuNTf2
Ph3PAuNTf2
AgOTf
Cu(OTf)2
Zn(OTf)2
In(OTf)3
Yb(OTf)3
Y(OTf)3
TsOH
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
PhCl, 808C, 2 h
toluene, 808C, 2 h
DCE, 808C, 2 h
PhCl, 808C, 2 h
76
55
84
87
86
78
88
91
36
18
90
87
99
<2
<2
10
<2
4
5
<2
3
<2
45
5
5
<1
9
10
11
12
13[c]
HOTf
Y(OTf)3
Y(OTf)3
Y(OTf)3
[a] Reaction conditions: [1a]=0.05 M. [b] Measured by 1H NMR spec-
troscopy using diethyl phthalate as internal standard. [c] Using 5 ꢀ
molecular sieves (M.S.; 30 mg/0.1 mmol) as an additive. DCE=1,2-
dichloroethane, Tf=trifluoromethanesulfonyl, Ts=4-toluenesulfonyl.
Ph3PAuNTf2 could indeed catalyze the putative hydroalkox-
ylation/Claisen rearrangement reaction to produce the
desired benzazocinone 2a in 76 and 55% yield, respectively
(entries 1 and 2). Somewhat surprisingly, it was found that
other non-noble metals could also be used to catalyze this
tandem reaction (entries 3–8), with Y(OTf)3 giving the best
yield of the desired 2a (entry 8). Notably, Brønsted acids[12]
such as TsOH and HOTf were not effective in promoting this
reaction (entries 9 and 10), and significant formation of
hydration product 2aa was observed in the latter case
(entry 10). Further screening of solvents such as toluene and
DCE led to a slightly decreased yield (entries 11 and 12).
Gratifyingly, 2a could be obtained in almost quantitative
yield by using 5 ꢀ molecular sieves as an additive (entry 13).
With the optimal reaction conditions in hand (Table 1,
entry 13), the scope of the reaction was explored. As shown in
Table 2, the reaction proceeded smoothly with different
sulfonyl-protected ynamides, thus affording the desired
[a] Reactions run in vials; [1]=0.05m. Yields of isolataed products are
reported. [b] The reaction was carried out on a 3.0 mmol scale with
5 mol% Y(OTf)3; [1a]=0.10 M.
benzazocinones 2a–d in almost quantitative yields
(entries 1–4; 2a was confirmed by X-ray diffraction).[14] In
addition, ynamides bearing different R2 groups also worked
very efficiently to produce the corresponding 2e–h (entries 5–
8). When R2 was either a styryl or alkyl group, the desired
product, 2i or 2j, respectively, was also formed in corre-
sponding yields of 81 and 87% yield (entries 9 and 10). Then,
various aryl-substituted ynamides were screened and the
reaction furnished the desired 2k–q in 82–99% yields
(entries 11–17). The reaction was also extended to other R1-
substituted ynamides, allowing the assembly of the corre-
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sponding 2r–w in 61–99% yields (entries 18–23). Notably,
also be extended to the preparation of the macrocycles 4j–l in
terminal ynamides also worked well to deliver products with
serviceable yields (entries 21 and 23). This cascade cyclization
is easy to scale-up. A gram-scale reaction of 1.38 grams of 1a
was carried out in the presence of 5 mol% of Y(OTf)3, thus
furnishing 1.38 grams of the desired 2a in 99% yield (entry 1).
Thus, this protocol provides a highly efficient and practical
route for the construction of benzazocinones.
This reaction was also extended to the substrate 1x, which
does not contain a terminal alkene tethered to the ynamide.
In this case, the corresponding benzazocinone 2x was
obtained as a single isomer with serviceable yield [Eq. (1)].
58–74% yields (entries 10–12). Of note, low concentrations
are necessary to circumvent the competing intermolecular
reaction in the case of the substrates 3k and 3l, and a small
amount of the 38-membered ring 4l’ was detected in the latter
case (entry 12).[13] The molecular structures of 4c, 4j, 4l, and
4l’ were confirmed by X-ray diffraction.[14]
In addition to ynamides, this cascade cyclization also
occurred efficiently with alkynyl ethers (5) by employing
Zn(OTf)2 as a catalyst, thus affording the desired eight-
membered benzolactones (benzoxocinones) 6a,b in high
yields [Eq. (2)]. Of note, this heterocyclic moiety is found in
a range of bioactive natural and non-natural products.[15]
Besides the formation of benzazocinones, this tandem
reaction was also viable for the construction of other valuable
medium-sized lactams. As depicted in Table 3, the reaction
worked efficiently with aliphatic ynamides, thus leading to the
formation of the corresponding functionalized azocinones
4a,b in excellent yields (entries 1 and 2). In addition, many 9-
to 11-membered medium rings can also be synthesized in 52–
97% yields (entries 3–9). Interestingly, this chemistry could
Further synthetic transformation of the as-synthesized
lactams was also explored (Scheme 2). For example, the Ts
group in the lactam 2a was easily removed upon treatment
Table 3: Reaction scope for the formation of other medium and large
ring lactams 4.[a]
Scheme 2. Transformation of selected benzazocinones. THF=tetrahy-
drofuran.
with SmI2 to give the corresponding 7a in 94% yield.
Interestingly, the use of NaBH4 combined with I2 led to the
selective reduction of the amide group to deliver the
benzazocine 7b in 91% yield. In contrast, both the amide
and ester groups of 2a were reduced to afford the benzazo-
cine 7c in 89% yield upon exposure to LiAlH4. Moreover, the
formal synthesis of the bioactive molecule 8b was achieved in
74% yield (2 steps) starting from the corresponding benz-
azocinone 2w by a facile hydrogenation of the double bond
and removal of the Ts group.
To probe the reaction mechanism, we first performed the
reaction in the presence of 5 equivalents of H218O and found
that no 18O was incorporated into the product, thus indicating
that the oxygen of the newly formed carbonyl group of
product 2a originates wholly from the hydroxy group of the
substrate 1a.[13] In addition, the product 2aa could not be
[a] Reactions run in vials; [3]=0.05m. Yields of isoalated products are
reported. [b] [3]=0.005m, 12 h. [c] 38-membered ring 4l’ was formed in
8% yield. Boc=tert-butoxycarbonyl.
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converted into 2a under the relevant reaction conditions, and
rules out 2aa as an intermediate on the way to 2a.[13,16]
Moreover, we prepared[13] and subjected 9 to the optimal
reaction conditions, and found that the reaction afforded the
corresponding [2+2] adduct 10 but not 2 [Eq. (3)], thus
indicating that the reaction pathway involving double
[1,5] hydride shift is less likely (Scheme 3, path b).[17] In
control experiments provide further evidence on the feasi-
bility of the proposed mechanism.
Acknowledgements
We are grateful for financial support from the NNSFC
(21622204, 21572186 and 21272191), the NSFFJ for Distin-
guished Young Scholars (2015J06003), the President
Research Funds from Xiamen University (20720150045),
and NFFTBS (No. J1310024). We also thank Prof. Dr. Xin Lu
(Xiamen University) for valuable discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclization · heterocycles · homogeneous catalysis ·
rearrangements · yttrium
Scheme 3. Plausible mechanism.
particular, it was found that the ketene aminal 11 f[13,18] could
be readily converted into the corresponding 2 f when sub-
jected to yttrium catalysis, thus strongly supporting that
[3,3] rearrangement was presumably involved in such
a tandem process [Eq. (4)].
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attacks the [Y]-activated ynamide 1a to afford the vinyl-
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may also be promoted by yttrium catalyst through coordina-
À
tion with the oxygen atom to facilitate the cleavage of C O
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hydroalkoxylation/Claisen rearrangement sequence, thus
leading to the highly efficient and atom-economical synthesis
of various valuable medium, and even, large ring lactams
from readily available ynamides. In addition, the construction
of eight-membered benzolactones can also be achieved by
a similar cascade cyclization of alkynyl ethers. Moreover,
4
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Manuscript received: January 17, 2017
Final Article published: && &&, &&&&
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Communications
Heterocycles
B. Zhou, L. Li, X.-Q. Zhu, J.-Z. Yan,
Y.-L. Guo, L.-W. Ye*
&&&& — &&&&
Yttrium-Catalyzed Intramolecular
Hydroalkoxylation/Claisen
Rearrangement Sequence: Efficient
Synthesis of Medium-Sized Lactams
Ring maker: An efficient yttrium-cata-
lyzed tandem intramolecular hydroxy-
alkylation/Claisen rearrangement has
been achieved, enabling facile access to
a diverse array of valuable medium-sized
lactams. A mechanistic rationale for this
novel reaction sequence is well supported
by a variety of control experiments.
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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