Metal-free Hydroalkoxylation-Formal [4+2] Cycloaddition Cascade for the Synthesis of Ketals

Article abstract of DOI:10.1002/chem.201701659

A transition metal free, acid promoted cascade hydroalkoxylation–formal [4+2] cycloaddition of various alkynols with salicylaldehyde is demonstrated for the synthesis of tetrahydrofurano/pyrano-chromenes and spiroketals. In general, alkynols underwent hydroalkoxylations in an endo-dig manner when internal alkynes were used to furnish the heteroannular ketals, whereas terminal alkynes proceeded in an exo-dig fashion leading to spiroketals. The study revealed that intramolecular hydroalkoxylation of alkynols is a preferred path over a generation of oxonium ions when coupling partner is salicylaldehyde. This metal-free transformation provides a new avenue for the stereoselective synthesis of tetrahydrofurano- and pyrano-chromenes in an expeditious manner.

Full text of DOI:10.1002/chem.201701659

A Journal of
Accepted Article
Title: Metal-free Hydroalkoxylation-Formal [4+2] Cycloaddition
Cascade for the Synthesis of Ketals
Authors: Santosh J. Gharpure, Santosh Kumar Nanda, Padmaja
Padmaja, and Yogesh Gangaram Shelke
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To be cited as: Chem. Eur. J. 10.1002/chem.201701659
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Supported by

10.1002/chem.201701659
Chemistry - A European Journal
COMMUNICATION
Metal-free Hydroalkoxylation-Formal [4+2] Cycloaddition Cascade
for the Synthesis of Ketals
Santosh J. Gharpure*, Santosh K. Nanda, Padmaja, Yogesh G. Shelke
O
Abstract:
hydroalkoxylation-formal [4+2] cycloaddition of various alkynols with
salicylaldehyde is demonstrated for the synthesis of
A
transition metal free, acid promoted cascade
Me
Me
O
Me
H
H
O
OH
Me
Me
Me
H
H
tetrahydrofurano/pyrano-chromenes and spiroketals. In general,
alkynols underwent hydroalkoxylations in an endo-dig manner when
internal alkynes were used to furnish the heteroannular ketals,
whereas terminal alkynes proceeded in an exo-dig fashion leading to
spiroketals. The study revealed that intramolecular hydroalkoxylation
of alkynols is a preferred path over a generation of oxocarbenium
ion formation when coupling partner is salicylaldehyde. This metal-
free transformation provides a new avenue for the stereoselective
synthesis of tetrahydrofurano- and pyrano-chromenes in an
expeditious manner.
Me
O
O
O
O
O
Me
Me
O
HO
O
Me
Me
O
H
Me
Xyloketal A (1)
Xyloketal D (2)
Alboatrin (3)
O
COOH
O
HO
MeO2C
O
OH
C7H15
OH
Me
Me
O
Me
O
O
O
C8H17
C5H11
Berkelic acid (5)
Paecilospirone (4)
Polycyclic heteroannular and spirocyclic ketal motifs are
frequently encountered in structurally complex natural products,
which display varied pharmacological and biological activity.[1]
Xyloketal A (1) belonging to xyloketal family acts as potent
inhibitor of acetylcholine esterase whereas alboatrin (3) inhibits
the root growth of the host plant and causes vascular-wilt
disease in alfalfa (Fig. 1).[2] Spiroketals such as paecilospirone
(4) act as potential antimitotic agent and berkelic acid (5)
exhibits selective activity against the ovarian cancer cell line.[3]
Biological activity of these natural ketals coupled with the
structural diversity has attracted attention of the synthetic
chemists and plethora of strategies have been developed for
their synthesis. In this context, significant progress has been
made on the synthesis of cyclic ketals using transition metal
catalysed bis-etherification via hydroalkoxylation of alkyne
diols.[4-6] Further, precious transition metal catalyzed
hydroalkoxylation of alkyne coupled with formal cycloaddition
reactions such as [4+2] or [3+2] have emerged as a method of
choice for the synthesis of oxygen containing heterocycles.[7-9]
While many of these approaches are elegant and efficient, they
require use of very costly metals such as gold and platinum
along with additives, which range from metals such as silver to
Brønsted acids, as well as higher reaction temperatures. Thus, a
transition metal free cascade process involving alkynols for the
synthesis of ketal derivatives is highly desirable. We disclose
herein one such approach where a Lewis or Brønsted acid can
be used not only to effect intramolecular hydroalkoxylation of an
alkynol at lower temperatures but also carry out formal [4+2]
cycloaddition with salicylaldehyde derivatives in a cascade
manner to furnish tetrahydrofurano/pyrano-chromenes bearing
tricyclic ketal frameworks in highly stereoselective manner. This
general approach also gives access to spirocyclic ketals.
Figure 1. Natural products bearing heteroannular and spirocyclic ketal motif.
In a programme directed at developing methods for synthesis of
various functionalized heterocycles,[10a-e] recently we disclosed a
Lewis acid promoted oxonium ion driven carboamination of
alkynes for the synthesis of cyclic ether-fused quinolines
(Scheme 1).[10f] Based on this study, we envisioned that alkynol
6 on reaction with salicylaldehyde (7) in the presence of Lewis/
Brønsted acid would furnish oxonium ion Int-A, which on
intramolecular formal [4+2] cycloaddition would afford cyclic
ether fused-chromene derivative 8. Interestingly, when such a
reaction was attempted with alkynol 6a and salicylaldehyde (7a)
using TMSOTf, the ketal 9a was formed rather than the
expected cyclic ether fused-chromene derivative 8a. This
observation could be explained by initial Lewis acid mediated
hydroalkoxylation leading to the intermediate Int-B, which upon
formal [4+2] cycloaddition gave rise to ketal 9a.[11]
Previous work: Oxonium ion driven carboamination for the synthesis
of cyclic ether-fused quinolines[10f]
Ph
Ph
Ph
CHO
N3
N3
N
TMSOTf
+
O
O
OH
Present work:
Ph
Ph
Lewis/
Brønsted
Acid
OH
O
O
O
Ph
OHC
HO
Int-A
8a
Our envisioned oxonium ion driven
carboalkoxylation of alkyne
OH
6a
7a
Ph
O
Ph
Lewis/
Brønsted
Acid
O
Int-B
O
9a
[a]
Dr. S. J. Gharpure, S. K. Nanda, Padmaja, Y. G. Shelke
Department of Chemistry
Indian Institute of Technology Bombay, Powai
Mumbai – 400076, India. Fax: +91-22-2576 7152; Tel: +91-22-2576
7171
Observed 5-endo-dig
hydroalkoxylation-formal [4+2] cycloaddition cascade
E-mail: sjgharpure@iitb.ac.in
Scheme 1. Proposed hydroalkoxylation-formal [4+2] cycloaddition cascade for
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.XXXXXXXX.
heteroannular ketal synthesis.
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Table 1. Scope of hydroalkoxylation-formal [4+2] cycloaddition cascade for the synthesis of tetrahydrofurano chromenes 9.
TMSOTf
R2
R3
or
OHC
HO
R2
TfOH
R1
+
R5
CH2Cl2, 0 °C
O
R5
O
R3
R4
R1 OH
R4
6
7
9
Yield (%),
dra
p-(NO2)-C6H4
o-Br-C6H4
Alkynol
Product
Entry
12
13
45b
O
6m
6n
6o
O
OH
9m
p-(NO2)-C6H4
Ph
98, 2:1b
75, 5.6:1c
Ph
Ph
1
O
Ph
O
6b
98b
OH
9b
O
O
OH
9n
o-Br-C6H4
Ph
Me
2
Me
83, 2:1b
6c
m-Br-C6H4
O
O
O
O
Ph
14
15
92b
9c
OH
O
O
OH
9o
Me
Me
m-Br-C6H4
Ph
Me
Me
95, 4:1b
85, 4.5:1c
nBu
3
4
5
6d
O
O
O
Me
OH
9d
Me
55, 2.5:1b
Ph
Ph
Ph
6p
O
O
9p
nBu
OH
Ph
86, 3.2:1b
82, 3.5:1c
Cy
Cy
6e
Ph
16
17
99b
OH
9e
6a
O
O
9q
Ph
OH
Ph
86, 4.5:1b
71, 4.5:1c
tBu
OMe
tBu
6f
Me
Me
O
Ph
Me
88, 4:1b
89, 4.5:1c
OH
9f
6d
O
H
O
H
OH
Me
Ph
Ph
Ph
9r
76, ≥19:1b
71, ≥19:1c
OMe
Ph
Ph
Ph
6
7
8
6g
O
H
Ph
O
Cy
H
OH
89, 3.2:1b
78, 4.5:1c
9g
9h
9i
Ph
Cy
18
19
O
6e
O
H
OH
H
9s
OMe
0d
tBu
Ph
79, 5.8:1b
76, 9:1c
6h
O
H
O
tBu
OH
H
Ph
O
6f
O
OH
H
9t
H
OMe
89, 2:1b
78, 4:1c
H
H
6i
67, ≥19:1b
61, ≥19:1c
O
H
O
Ph
OH
H
Ph
20
6g
O
H
O
Me
Ph
Me
H
OH
9u
OMe
Ph
9
98, 10:1b
6j
Ph
O
O
21
22
91b
OH
9j
6k
Ph
O
O
OH
Ph
9v
Ph
OMe
6k
10
11
94b
79,10:1b
52,10:1c
Ph
O
O
9k
tBu
OH
tBu
Ph
6f
O
O
OMe
9w
OH
Ph
p-OMe-C6H4
H
H
56b
60, ≥19:1b
60, ≥19:1c
6l
O
O
Ph
OH
9l
23
p-OMe-C6H4
6g
O
H
O
OMe
H
OH
9x
Ph
[a]In all the cases dr was obtained on crude reaction mixture by 1H NMR analysis, [b]reaction was carried out with TMSOTf, [c]reaction was carried out with TfOH,
[d]starting materials were recovered back.
This unusual reaction outcome prompted us to explore transition
metal-free tandem hydroalkoxylation-cycloaddition reaction for
the synthesis of ketal derivatives 9.
studies.[12] Further scope and limitation of the method was then
investigated using both the methods A and B. While changing
substituents on alkynol next to OH group (R1) had little effect on
the yield, the diastereoselectivity was found to improve as the
substituent became bulkier. It was found that alkynol bearing
tert-butyl group (6f) offered better diastereoselectivity for the
formation of the corresponding chromene ketal (9f) than that
observed for alkynols with methyl (6c), isopropyl (6d) or
cyclohexyl (6e) group (Table 1, entry 2-5). The trans alkynyl
cyclohexanol 6g gave excellent diastereoselectivity for the
formation of the chromene 9g. Interestingly, when ‘cis’ alkynyl
cyclopentanol 6i was used, the product ketal 9i was obtained in
excellent yield, unlike the ‘trans’ alkynol 6h, albeit with moderate
Study of the reaction scope commenced by treatment of alkyn-1-
ol 6b with salicylaldehyde (7a) in the presence of TMSOTf (2
equiv.). Gratifyingly the ketal 9b was obtained in excellent yield,
albeit with moderate diastereoselectivity [Method A] (Table 1,
entry 1). To improve diastereoselectivity, various Lewis/Brønsted
acids were screened (see, supporting information). It was found
that use of TfOH (2 equiv.) in CH2Cl2 at 0 oC resulted in
formation of the ketal 9b with improved diastereoselectivity
[Method B]. Stereochemistry of the major diastereomer was
assigned as ‘cis’ based on the single crystal X-ray diffraction
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Table 2. Synthesis tetrahydropyrano chromene.
also tested with different alkynols and in all the cases desired
chromene derivatives 9q-x were obtained in excellent yield
(Table 1, entry 16-23). In all the cases, the stereochemistry of
the major cis-isomer was assigned based on NOESY or NOE
experiments. It was further confirmed from single crystal X-ray
diffraction studies on the 9d, 9e, 9t and 9u.[12]
R2
R2
OHC
+
O
TMSOTf
+
R1
2 R1
O
O
CH2Cl
0 °C
OH
R2
O
HO
H
R1
11
7a
12
13
Synthesis of tetrahydropyrano chromene derivatives 12 was
studied next. Pentyn-1-ol (11a) on reaction with salicylaldehyde
(7a) furnished the tetrahydropyrano chromene 12a as the major
product along with the chromene 13a formed by alkyne Prins
type cyclization – intramolecular vinyl cation trapping cascade
(Table 2, entry 1). The alkynol 11b with aryl ring substituted with
electron withdrawing NO2 group also furnished a mixture of the
chromene ketal 12b (55%) and pyrano chromene 13b (45%)
with poor selectivity. However, alkynols 11c-d bearing electron
releasing substituents on the aryl ring led to exclusive formation
of the chromene ketals 12c-d, respectively (Table 2, entry 3-4).
Interestingly, alkyl substituted alkynol 11e upon reaction with
salicylaldehyde (7a) furnished the pyrano chromene 13e along
with only trace of chromene ketal 12e (Table 2, entry 5). There
appears to be a delicate balance between the two possible
reaction paths, viz. hydroalkoxylation-formal [4+2] cycloaddition
v/s alkyne Prins type reaction-vinyl cation trapping. In the cases
where vinyl cation is stabilised, former seems to dominate
whereas if this intermediate is destabilised, the latter path
competes. It should also be noted that the 5-endo-dig reactions
of alkynes are faster than the corresponding 6-endo-dig
cyclization and hence no such competing product formation was
observed in the case of alkynols 6. This was further
corroborated by reaction of the aryl fused alkynols 11f and 11g,
which exclusively furnished the chromene ketals 12f and 12g,
respectively, in quantitative yield (Table 2, entry 6-7). Here, due
to lower conformational flexibility of the alkynols, the
intramolecular 6-endo-dig hydroalkoxylation was significantly
faster than the competing intermolecular oxonium ion formation,
which resulted in the eventual formation of the chromene ketals
(cf. Scheme 1).
Entry
Alkynol
Product
Ph
Ph
O
+
1
11a
OH
O
O
12a
O
13a
Ph
69%
25%
C6H4-(NO2)-p
p-(NO2)-C6H4
11b
O
+
2
3
4
5
O
12b
55%
O
O
OH
13b
45%
p-(NO2)-C6H4
C6H4-OMe-p
p-OMe-C6H4
O
+
11c
O
O
O
OH
12c
13c
0%
p-OMe-C6H4
78%
C6H4-Me-p
p-Me-C6H4
O
+
11d
O
O
O
OH
12d
p-Me-C6H4
13d
89%
0%
nBu
O
nBu
11e
OH
+
H
Me
O
O
12e
trace
O
nBu
13e
65%, 15:1
Me
Me
Ph
O
Ph
+
6
7
O
11f
OH
Ph
O
12f
13f
O
97%
0%
Table 3. Synthesis of spirocyclic ketals 15.
Ph
O
OHC
Ph
TMSOTf
+
O
11g
OH
+
Ph
12g
CH2Cl2, 0 °C
O
OH
HO
O
O
13g
0%
14
7a
15
O
Me
Me
97%, 3:1
Entry
Alkynol
Product
Me
diastereoselectivity [Method B] (Table 1, entry 7-8). The alkynol
6j bearing methyl substitution on second carbon gave a much
better diastereoselectivity for formation of the ketal 9j (Table 1,
entry 9 v/s entry 2). It is pertinent to note that tertiary alcohol 6k
too was tolerated under reaction conditions employed and the
spirocyclic ketal 9k was obtained in excellent yield (Table 2,
entry 10). Interestingly, both the alkynols 6l-m having either
electron donating or electron withdrawing group on the aryl ring
gave lower yield of the chromene 9l and 9m, respectively (Table
2, entry 11-12). While competing formation of the keto alcohol
10 [4-hydroxy-1-(4-methoxyphenyl)butan-1-one] due to net
hydration of alkyne was the reason for lower yield in the former
case, lower stability of the vinyl cation was responsible in the
latter. On the other hand, alkynols 6n-o with bromide substituent
on the aryl ring gave desired chromenes 9n-o in near
quantitative yield (Table 1, entry 13-14). The reaction of aliphatic
alkynol 6p gave the ketal 9p in only moderate yield and
diastereoselectivity (Table 1, entry 15). Salicylaldehyde
derivatives bearing electron releasing substituents (7b-c) were
1
2
3
O
OH
O
14a
15a, 76%
OH
O
O
14b
15b, 68%
O
OH
O
15c, 97%
14c
nBu
nBu
4
OH
14d
O
O
15d, 83%
The hydroalkoxylation of alkyne-formal [4+2] cycloaddition
cascade was also studied with terminal alkynols 14. To begin
with, pentyn-1-ol (14a) was coupled with salicylaldehyde (7a)
using TMSOTf. Interestingly, hydroalkoxylation step proceeded
in a 5-exo-dig manner leading to the spirocyclic ketal 15a, albeit
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requiring longer reaction time (Table 3, entry 1). This reaction
was found to be general and alkynols 14b-c gave the spirocyclic
ketals 15b-c in good yield (Table 3, entry 2-3). Interestingly,
when aliphatic alkynol 14d was subjected to reaction with
salicylaldehyde (7a) under optimized conditions, the spirocyclic
ketal 15d was obtained as the only detectable product (Table 3,
entry 4). The structure of spirocyclic ketal 15d was confirmed
based on the NMR correlation experiments (see, supporting
information for details). This strategy can be potentially used in
the total synthesis of spiroketal natural products such as
paecilospirone (4).
give an opportunity to compare reactivity of hydroalkoxylation
and Prins cyclization of olefin through oxonium ion. When
alkynol 6r was subjected to reaction with salicylaldehyde (7a)
under optimized conditions using TMSOTf, bicyclic ether 24 was
obtained as exclusive product through conventional alkene Prins
cyclization followed by trapping of the tertiary carbocation
intermediate by phenolic OH. The alkynol 6q on the other hand
gave the ketal 9y in good yield via tandem hydroalkoxylation-
formal [4+2] cycloaddition process, further demonstrating that
subtle conformational changes can significantly influence the
reaction pathway (Scheme 3). It was envisaged that synthesis of
oxa- or aza-cycle fused tetrahydrofurano chromenes would be
challenging. Towards this end, the alkynols 25 and 26 were
treated with salicylaldehyde (7a) using optimized reaction
condition to furnish the products 27 (dr ≥ 19:1) and 28 (dr 5:1),
respectively, in excellent yields.[13]
( )n
R
Path B
Path A
TMSOTf
( )
O
nO
TMSOTf
H
n = 1,2
R = H/alkyl
5-exo-dig
n = 0
R = alkyl/aryl
5-endo-dig
n = 1, R = aryl
6-endo-dig
17
O
OH
( )n
R
R
H
OH
16
11 or 14
O
Ph
Ph
OH
Ph
6r
6q
Mukaiyama Aldol
type reaction
Mukaiyama Aldol
type reaction
OH
OH
7a
O
TMSOTf
CH2Cl2, 0 °C
94% (dr >19:1)
TMSOTf
CH2Cl2, 0 °C
89% (dr 2:1)
O
OH
H
OH
R
O
O
Ph
9y
HO
HO
24
R
O
O
O
O
H
H
Ph
R
O
O
R
H
O
OHC
H
O
( )n
( )n
19
- H2O
( )n
O
( )n
O
TMSOTf
21
- H2O
20
+
18
O
CH2Cl2, 0 °C
85%, dr > 19:1
HO
- H2O
- H2O
OH
25
O
Ph
H
7a
27
H
Ph
Ph
O
OHC
Ph
N
H
TMSOTf
N
R
O
+
O
O
R
O
R
O
CH2Cl2, 0 °C
95%, dr 5:1
R
HO
O
O
H
O
O
O
O
( )n
( )n
( )n
9/12
( )n
OH
Ph
28
26
7a
23
15
22
6π-electrocyclic
ring closure
6π-electrocyclic
ring closure
Scheme 3. Synthesis of bicyclic ether and cyclohexene/tetrahydropyran/
pyrrolidine-fused tetrahydrofurano chromenes.
Scheme 2. Mechanism of formation of chromene ketals.
To further expedite the synthesis of tetrahydropyrano chromene
derivatives, a ‘one pot’ protocol involving even generation of the
requisite alkynol in the same flask was attempted. Alkynal 29
was subjected to allylation using allyltributylstannane (30) and
BF3×OEt2 in CH2Cl2 followed by addition of 1 equiv. of water.
Salicylaldehyde (7a) and TMSOTf were added sequentially to
the same reaction mixture to furnish the chromene ketal 31 in
excellent overall yield with moderate diastereoselectivity
(Scheme 4). It is interesting to note that the reaction sequence
was successful only when 1 equiv. of water was added in order
to hydrolyse tin alkoxide intermediate.
Mechanistically, diverse outcomes of the varied chromene
formations starting from alkynols and salicylaldehyde derivatives
7
can be explained by two competing paths viz.
hydroalkoxylation v/s oxonium ion formation (vide supra).
Further, regioselectivity of hydroalkoxylation decides whether
linearly-fused or spirocyclic chromene would form as the product
(Scheme 2). When homopropargyl alcohols are used, the
hydroalkoxylation proceeds in a 5-endo-dig (rather than 4- exo-
dig) fashion (Path A). Since the 5-endo-dig mode of
hydroalkoxylation is very facile, the oxonium ion formation does
not seem to compete and tetrahydrofurano chromenes 9 are
formed as exclusive products. While bis-homopropargyl internal
alkynols undergo hydroalkoxylation in 5/6-endo-dig manner
(Path A), terminal ones proceed through 5/6-exo-dig mode (Path
B). The internal alkynol with alkyl substitution on the aryl alkyne
(e.g. alkynol 14d) prefer the 5-exo-dig cyclization, perhaps due
to extra stability of benzylic vinyl cation. The vinyl ethers 16 and
17 formed by hydroalkoxylation undergo Mukaiyama aldol
reaction with salicylaldehyde to form oxonium ions 18 and 19,
respectively. The oxonium ions 18 and 19 lead to chromenes
9/12 and 15, either by their trapping by phenolic OH followed by
water elimination or their rearrangement to dienones 22 and 23,
respectively, followed by 6-electrocyclic ring closing reaction.
During the study of substrate scope, it was envisioned that
substrate like enynol 6q/6r would be interesting as they would
SnBu3
30
Ph
i. BF3⋅OEt2, CH2Cl2
O
-78 °C
O
ii. 1 equiv. H2O
CHO
29
iii. salicylaldehyde (7a)
31
iv. 2 equiv. TMSOTf
79%, 4.5:1
Scheme 4. ‘One Pot’ allylation-hydroalkoxylation of alkyne-formal [4+2]
cycloaddition.
Finally, to enhance the utility of our established protocol, bis-
alkynol 32 was treated with 2 equiv. of salicylaldehyde (7a) to
afford bis-chromene derivative 33 in 78% yield as a ca. 1:1
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d) M. H. H. Nkunya, R. Waibel, H. Achenbach, Phytochemistry 1993,
34, 853-856.
mixture of diastereomers. At this juncture, we thought that this
strategy could be extended to a sequence involving two reaction
mechanisms viz. hydroalkoxylation of alkyne-formal [4+2]
cycloaddition as well as oxonium ion driven carboamination in a
‘one pot’ manner to rapidly build structural complexity. To
demonstrate this concept, bis-alkynol 32 was reacted with 1
equiv. salicylaldehyde (7a) followed by azido aldehyde 34 [after
starting material was consumed in the first step (TLC control)],
which indeed gave the quinoline chromene derivative 35 in good
yield (Scheme 5).[10f]
[3]
[4]
a) M. Namikoshi, H. Kobayashi, T. Yoshimoto, S. Meguro, Chem. Lett.
2000, 308-309. b) A. A. Stierle, D. B. Stierle, J. Org. Chem. 2006, 71,
5357–5360.
Transition metal catalysed synthesis of heteroannular ketals: a) H. X.
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O
O
HO
7a (1 equiv.)
O
TMSOTf
CH2Cl2
0 °C
O
O
O
7a (2 equiv.)
TMSOTf
meso-33
+
then
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CHO
CH2Cl2
0 °C
78% (dr 1:1)
N
32
O
O
N3
O
O
34
59%
O
35
HO
dl-33
Scheme 5. ‘One pot’ synthesis of bis-chromene 33 and quinoline chromene
derivative 35.
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Acknowledgement: We thank SERB, New Delhi for financial
support. We thank Mr. Darshan Mhatre of the X-ray facility of the
Department of Chemistry, IIT Bombay for collecting the
crystallographic data and IRCC, IIT Bombay for funding central
facilities. We are grateful to CSIR, New Delhi for the award of
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Keywords: Hydroalkoxylation • Lewis/Brønsted acid catalysed
reactions • Cyclic ether-fused chromenes • [4+2] cycloaddition •
Linear/spirocyclic Ketal
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Santosh J. Gharpure*, Santosh K.
Nanda, Padmaja, Yogesh G. Shelke
Page No. – Page No.
Metal-free Hydroalkoxylation-Formal
[4+2] Cycloaddition Cascade for the
Synthesis of Ketals
Lewis/Brønsted acid mediated stereoselective synthesis of chromene ketals is
demonstrated. The cascade reaction involved transition metal free hydroalkoxylation
of alkyne-formal [4+2] cycloaddition with salicylaldehyde. Complex scaffolds like bis-
chromene, quinoline-fused chromene, core of xyloketal and paecilospirone natural
products could be assembled employing this method. The study suggested that
substituents on alkyne govern exo v/s endo mode of hydroalkoxylation of alkynols to
furnish polycyclic heteroannular or spirocyclic chromene ketals.
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