Hauser–Kraus Annulation of Phthalides with Nitroalkenes for the Synthesis of Fused and Spiro Heterocycles

Article abstract of DOI:10.1002/ejoc.201600390

Hauser–Kraus annulation of sulfonylphthalides with simple conjugated nitroalkenes follows the expected pathway to furnish naphthoquinones in moderate yields. However, a strategic variation of this reaction by employing nitroalkenes bearing an additional nucleophilic site results in [4+4] annulation leading to complex fused and spiro heterocycles in high yields with high selectivity through a cascade process involving Michael addition, Dieckmann cyclization, and a series of eliminations and rearrangements.

Full text of DOI:10.1002/ejoc.201600390

DOI: 10.1002/ejoc.201600390
Communication
Spiro Compounds
Hauser–Kraus Annulation of Phthalides with Nitroalkenes for
the Synthesis of Fused and Spiro Heterocycles
Tarun Kumar,[a] Nishikant Satam,[a] and Irishi N. N. Namboothiri*[a]
Dedicated to Professor Dipak Ranjan Mal, IIT Kharagpur[‡]
Abstract: Hauser–Kraus annulation of sulfonylphthalides with tion leading to complex fused and spiro heterocycles in high
simple conjugated nitroalkenes follows the expected pathway yields with high selectivity through a cascade process involving
to furnish naphthoquinones in moderate yields. However, a Michael addition, Dieckmann cyclization, and a series of elimi-
strategic variation of this reaction by employing nitroalkenes nations and rearrangements.
bearing an additional nucleophilic site results in [4+4] annula-
Introduction
Michael addition/Dieckmann cyclization/elimination sequence
in an overall [4+2] annulation has been extensively exploited
for the synthesis of complex molecules, including natural prod-
ucts.[9–11]
Spiro heterocycles display unique properties that are relevant
to areas as diverse as biology and materials science and are
present in many natural products.[1] This is primarily due to
their conformationally rigid structures, in which one carbon
atom is shared by two orthogonal rings, often both heterocy-
clic. Spiro(benzofuran-isobenzofuran) is such a scaffold, and it
is present in influenza virus type B inhibitors[2] and fluorescent
probes (Figure 1).[3] Spiro heterocycles often arise from fused
multi-heterocycles, which in their own right are synthetic inter-
mediates and biological agents. For instance, benzoindeno-
[1,2-b]furans[4] exhibit antiviral properties[5] and undergo rear-
rangement to the spiro(benzofuran-isobenzofuran) skeleton.[2,3]
Numerous functional groups at the 3-position of phthalide
(benzofuranone) 1, such as sulfonyl, carboxylate, and phos-
phonate, facilitate the base-mediated deprotonation of the
phthalide, stabilization of the anion, and Dieckmann-type cycli-
zation of Michael adduct I as a result of the Thorpe–Ingold
effect; aromatization through elimination to give quinone 3 has
contributed to the development of this elegant benzannulation
protocol (Scheme 1, a).[8,10] Michael acceptors 2, in general, are
α,ꢀ-unsaturated carbonyl compounds, though vinyl sulfones
and nitroalkenes have also been employed.[8]
Figure 1. Fused and spiro benzofuran-containing bioactive compounds.
Annulation of stabilized phthalide anions with various
Michael acceptors, popularly known as the Hauser–Kraus (H–K)
reaction, is an attractive strategy for the synthesis of benzannu-
lated quinones, especially naphthoquinones.[6–8] The 1,4-dipolar
reactivity of phthalide with a Michael acceptor involving a
[a] Department of Chemistry, Indian Institute of Technology,
Bombay, Mumbai 400 076, India
E-mail: irishi@iitb.ac.in
www.chem.iitb.ac.in/~irishi
Scheme 1. H–K reaction of phthalides with acceptors.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600390.
[‡] In honor of his pioneering contributions to the Hauser–Kraus annulation
As for the participation of nitroalkenes in the H–K reaction,
annulation of an L-fucose-derived nitroglycal with a sulfon-
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ylphthalide was shown to lead to the formation of (+)- indenofuran 7a (78 %; Table 1, entry 1), the structures of which
cryptosporin, a pyranonaphthoquinone-containing fungal met- were confirmed by detailed NMR spectroscopy analysis and fur-
abolite, with loss of the nitro group.[11] Similarly, a substituted ther were unambiguously established by single-crystal X-ray
nitrostyrene was reported to undergo annulation with a cyano- analysis (see below). Upon changing the base to Cs2CO3
phthalide to afford a naphthoquinone bearing a nitro group.[12] (2 equiv.), a larger amount of spiro-lactone 6a (20 %) was iso-
Recently, a quinine–thiourea-catalyzed reaction of various lated with a concomitant decrease in the yield of indenofuran
nitroalkenes with phthalide ester provided the Michael adducts 7a (47 %; Table 1, entry 2). Decreasing the amount of Cs2CO3
in excellent yields and selectivities but did not lead to cycliza- to 1 equiv. restored the favorable formation of 7a (75 %;
tion.[13]
In view of the unpredictable nature and the limited attention
Table 1, entry 3). The reaction was improved further almost
exclusively in favor of 7a (81 %) by lowering the quantity of
Cs2CO3 to 0.5 equiv. (Table 1, entry 4). Amine bases such as
Et3N and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were not
suitable for our reaction (Table 1, entries 6 and 7). Furthermore,
Cs2CO3 did not perform well in other solvents such as CH2Cl2
and toluene (Table 1, entries 8 and 9).
paid to the H–K annulation of phthalides 1 with nitroalkenes 2
(E2 = NO2),[14] at first, we intended to investigate the annulation
of a phthalide such as sulfonylphthalide 1 (E1 = SO2R) with
selected nitroalkenes 2 (E2 = NO2). More importantly, we con-
ceptualized that the poor nucleophilicity of the nitronate aris-
ing from Michael addition was responsible for the limited suc-
cess of attempted annulations involving nitroalkenes. We
wished to take advantage of the reluctance of nitronates to
undergo cyclization by installing another nucleophilic site in
nitroalkenes 2, which would thereby alter the course of the
reaction (Scheme 1, b). Thus, Dieckmann-type cyclization of in-
termediate Michael adduct II by intramolecular attack of the
nucleophilic X– site on the lactone carbonyl would provide
bridged [4+4] annulation product III, which appeared suscepti-
ble to ring opening and elimination. This hitherto unexplored
pathway in the H–K reaction offered us a unique opportunity
to construct bridged/fused and spiro heterocyclic scaffolds.
Table 1. Optimization of the reaction conditions.[a]
Entry
Base (equiv.)
Solvent
Time
[h]
Yield[b] [%]
6a
7a
1
2
3
4
5
6
7
8
9
K2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.0)
Cs2CO3 (0.5)
Cs2CO3 (0.2)
Et3N (2.0)
DBU (2.0)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
24[c]
2
4
12
24
–
–
24
24
10
20
14
78
47
75
Results and Discussion
Our preliminary investigations on the conventional H–K annula-
tion of sulfonylphthalide 1a with various nitrostyrenes 2 was
met with only limited success, as a mixture of expected [4+2]
annulation product quinone 3 with the loss of a nitro group in
moderate yield (40–52 %) and Michael adduct 4 in low yield
(0–11 %) was isolated (Scheme 2, see also the Supporting Infor-
mation). At this juncture, we envisioned that introduction of an
additional nucleophilic site at the ortho position of the aromatic
ring in nitrostyrene 2 would open up a competitive but more
rewarding reaction pathway through 1,4-nucleophile–electro-
phile reactivity of both the substrates leading to a [4+4] annula-
tion product.
trace
–
81
[d]
–
[e]
[e]
[e]
[f]
–
–
–
–
–
–
[e]
[f]
–
–
[f]
[f]
[a] Reaction scale: 5a (0.3 mmol), 2a (0.33 mmol, 1.1 equiv.). [b] After silica
gel column chromatography. [c] Conversion ca. 90 %. [d] Conversion ca. 65 %.
[e] No reaction. [f] Complex mixture.
The proposed mechanism for the formation of 6a and 7a
begins with Cs2CO3-mediated deprotonation of 1a to form sta-
bilized anion IV, which adds in a Michael fashion to 5a to form
intermediate V, the Michael adduct (Scheme 3). Initial cycliza-
tion (trans-lactonization or Dieckmann cyclization) of V (as
shown in Vb) gives oxa-bridged intermediate VI in an overall
[4+4] annulation process, which then eliminates the sulfonyl
group to afford eight-membered ketolactone VII. Base-medi-
ated elimination of HNO2 from VII provides intermediate VIII,
which is a good Michael acceptor. This incipient Michael ac-
ceptor undergoes counter attack by the sulfonate still present
in the medium followed by intramolecular 5-exo-trig cyclization
to furnish fused product 7a, which possesses keto, sulfonyl, and
cyclic hemiacetal functionalities.
Scheme 2. H–K reaction of phthalide with nitroalkenes.
At the outset, o-hydroxynitrostyrene (5a) was chosen as the
model substrate to evaluate our new concept of [4+4] annula-
tion with phthalide 1a (Table 1). The base, K2CO3, which was
found suitable for the synthesis of quinones 3 and Michael ad-
In the presence of an excess amount of base, ring opening
ducts 4, was first employed in THF for the reaction of nitro- of 7a generates eight-membered lactone IX, which undergoes
alkene 5a with phthalide 1a. Much to our amusement, the ring contraction to five-membered lactone X through trans-
product contained a mixture of spiro-lactone 6a (10 %) and lactonization (Scheme 4). Ring-oxygen-assisted elimination of
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Scheme 3. Plausible mechanism for the formation of indenofuran.
the sulfonyl group from X to generate zwitterionic intermediate
XI followed by intramolecular cyclization in a 5-exo-trig fashion
by attack of the phenoxide ion provides spiro-lactone 6a.[15]
Table 2. Scope of the o-hydroxynitrostyrenes.[a,b]
Scheme 4. Plausible mechanism for the rearrangement of indenofuran to
spiro-lactone.
[a] Reaction scale: 5 (0.4 mmol), 1a (0.44 mmol), and Cs2CO3 (0.2 mmol,
0.5 equiv.). [b] Yields after silica gel column chromatography. [c] Cs2CO3
(1.0 equiv.) was used (only 50 % conversion with 0.5 equiv. of Cs2CO3) and
besides indenofuran 7g, spiro-benzofuran 6g was isolated in 12 % yield.
After confirming Cs2CO3 (0.5 equiv.) in THF at room tempera-
ture as the optimal condition for the reaction (Table 1, entry 4),
the reactivity of various o-hydroxynitrostyrenes 5 was investi-
Subsequently, various sulfonylphthalides 1 were screened for
gated for the synthesis of benzo[d]indeno[1,2-b]furans
7
the reaction, and the results are summarized in Table 3. Benzo-
(Table 2). The reaction of nitroalkene 5a with phthalide 1a af- indenofurans 7h–j were isolated in very high yields (84, 80, and
forded benzoindenofuran 7a in 81 % yield. Nitroalkenes 5b– 77 %, respectively) upon employing sulfonylphthalides 1b–d
d bearing electron-donating substituents on the aromatic ring bearing electron-withdrawing substituents on the aromatic ring
furnished products 7b–d in good yields (68, 74, and 68 %, re- of the arenesulfonyl for the reaction with nitroalkene 5a. Sulf-
spectively). Substrates 5e and 5f bearing electron-deficient aryl onylphthalides 1e and 1f bearing electron-donating groups on
groups afforded products 7e and 7f in slightly improved yields the aromatic ring of the arenesulfonyl also afforded products 7k
(75 and 73 %, respectively). Naphthyl derivative 5g was less re- and 7l in good yields (70 and 74 %, respectively). 2-Naphthyl-
active under the optimized conditions with only 50 % conver- substituted sulfonylphthalide 1g was also well tolerated, and
sion, and therefore, the reaction was performed with 1.0 equiv. product 7m was isolated in 63 % yield. After successful demon-
of Cs2CO3 to obtain product 7g in 50 % yield along with 12 % stration of the reactivity of diverse arylsulfonylphthalides 1a–
of corresponding spiro-benzofuran 6g.
g, various alkylsulfonylphthalides 1h–j were screened for the
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reaction. Cyclic as well as branched and linear aliphatic sulfonyl-
The above optimized conditions were employed for the rear-
phthalides 1h–j took part in the reaction, and products 7n–p rangement of various indenofurans 7 into spiro-lactones 6
were isolated in respectable yields (59–69 %).
(Table 5). Indenofuran 7a and para-methyl (with respect to the
benzofuran oxygen atom) analogue 7d delivered spiro-lactones
6a and 6d in identical yields (72 %) and reaction times (6 h).
Whereas meta-methoxy analogue 7b was the best in terms of
product yield (79 % for 6b), the yields of ortho-ethoxy and
naphthyl analogues 6c and 6g were also good (69 and 71 %,
respectively). Although the reaction of para-bromo analogue
6g was complete within the shortest timeframe (5 h), the yield
of product 6e was moderate (52 %).
Table 3. Scope of sulfonylphthalides.[a,b]
Table 5. Rearrangement of indenofurans into spiro-lactones.[a,b]
[a] Reaction scale: 5a (0.4 mmol), 2 (0.44 mmol), and Cs2CO3 (0.2 mmol).
[b] Yields after silica gel column chromatography.
Surprisingly, upon subjecting indenofuran 7a to O-methyl-
ation by using MeI under standard basic conditions, that is, in
the presence of K2CO3 in acetone under reflux, instead of the
expected O-methylated product, we isolated spiro-lactone 6a.
This suggested that the mechanism depicted in Scheme 2 for
the formation of spiro-lactone 6 through rearrangement of in-
denofuran 7 was justified and that the smooth transformation
of 7 into 6 was indeed feasible. Therefore, we systematically
optimized the reaction conditions for the rearrangement of 7a
into 6a (Table 4). First, with 1 equiv. of K2CO3 in acetone under
reflux for 20 h, product 6a was isolated in 60 % yield (Table 4,
entry 1). Increasing the amount of base to 2.5 equiv. favored a
cleaner reaction at shorter time (6 h) and yielded spiro-lactone
6a in higher yield (72 %; Table 4, entry 2). Increasing the
amount of base to 3.5 equiv. (Table 4, entry 3) or changing the
base to Cs2CO3 (Table 4, entry 4) resulted in a decrease in the
reaction time but did not improve the yield. Upon changing
the solvent to THF, the reaction took 8 h for completion, and
product 6a was formed in 68 % yield (Table 4, entry 5). Further-
more, the reaction did not proceed at room temperature even
after 24 h (Table 4, entry 6).
[a] Reaction scale: 7 (0.1 mmol) and K2CO3 (0.25 mmol). [b] Yields after silica
gel column chromatography.
In the mechanism for the formation of indenofuran 7 from
phthalide 1 and nitroalkene 5, departure of the sulfonyl group
from intermediate VI and subsequent intermolecular Michael
addition of the sulfonyl group to incipient enone VIII was pro-
posed (Scheme 3). To gain additional insight into this mecha-
nism, a control experiment between sulfonylphthalide 1a and
o-hydroxynitrostyrene (5a) in the presence of an equimolar
amount of sodium 4-methylbenzenesulfinate (8) was per-
formed (Scheme 5). Analysis of the crude reaction mixture by
1H NMR spectroscopy, after completion of the reaction, showed
the formation of indenofurans 7a and 7l bearing phenylsulfonyl
and p-toluenesulfonyl groups, respectively, in a ratio of ca.
40:60.
Table 4. Optimization studies.[a]
Entry
Base (equiv.)
Solvent
T [°C]
Time [h]
Yield[b] [%]
1
2
3
4
5
6
K2CO3 (1)
acetone
acetone
acetone
acetone
THF
56
56
56
56
56
r.t.
20
6
5
4
8
60
72
65
K2CO3 (2.5)
K2CO3 (3.5)
Cs2CO3 (3.5)
K2CO3 (2.5)
K2CO3 (2.5)
Scheme 5. Mechanistic studies.
60
68
acetone
24
trace[c]
Formation of p-toluenesulfonyl-substituted indenofuran 7l
confirmed the participation of the sulfonate as an external nu-
cleophile and the involvement of eight-membered enone VIII
[a] Reaction was performed with 0.1 mmol of 7a. [b] After silica gel column
chromatography. [c] Most of the starting material was recovered.
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and 4, and spiro-lactone 6a was isolated in good yield (52 %).
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Scheme 6. One-pot reaction.
Conclusion
In conclusion, the [4+2] annulation of phthalides with conju-
gated nitroalkenes typically provides the expected substituted
naphthoquinones in moderate yields. However, the presence
of additional nucleophilic sites in the nitroalkene changes the
reaction course to a [4+4] annulation, the first observation in
Hauser–Kraus chemistry, and delivers functionalized fused and
spiro heterocycles in good to excellent yields after extensive
rearrangement. Studies aimed at gaining greater insight into
the mechanism of the observed multicascade processes and at
expanding the scope and applications of the products are cur-
rently underway in our laboratory.
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CCDC 1455012 (for 6b) and 1455013 (for 7a) contain the
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Supporting Information (see footnote on the first page of this
article): Complete experimental procedures, characterization data,
and copies of the NMR spectra for all new compounds.
Acknowledgments
I. N. N. N. thanks Science and Engineering Research Board
(SERB), Department of Science and Technology (DST), India, for
financial assistance. T. K. thanks the Council of Scientific and
Industrial Research (CSIR), India, and N. S. thanks the University
Grants Commission (UGC), India, for a senior research fellow-
ship.
Keywords: Annulation · Fused-ring systems · Spiro
compounds · Oxygen heterocycles · Nitroalkenes
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n) furans: V. Mane, T. Kumar, S. Pradhan, S. Katiyar, I. N. N. Namboothiri,
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[15] For a similar skeletal rearrangement, see ref.[2,3]
Received: March 29, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Spiro Compounds
A [4+4] Hauser–Kraus annulation of
sulfonylphthalides
with
phenolic
T. Kumar, N. Satam,
I. N. N. Namboothiri* ........................ 1–7
nitrostyrenes to indenofurans and re-
arrangement of the latter to spiro-
(benzofuran–isobenzofuran)s is de-
scribed.
Hauser–Kraus Annulation of Phthal-
ides with Nitroalkenes for the
Synthesis of Fused and Spiro
Heterocycles
DOI: 10.1002/ejoc.201600390
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www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim