Organophosphine-catalyzed intramolecular hydroacylation of activated alkynes

Article abstract of DOI:10.1021/acscatal.8b00397

We present the details of an organophosphine-catalyzed Morita-Baylis-Hillman-type reaction of activated alkynes. The outcome is an intramolecular hydroacylation of α,β-ynones leading to the formation of 1,3-cyclopenta-, cyclohepta-, and cyclooctadione-fused arenes and heteroarenes. In addition, during the course of the investigation, a phosphine-catalyzed intramolecular aldol reaction of keto-ynones via δ′[C(sp³)-H]-functionalization was discovered, and a new annulation event comprising of a ω′[C(sp³)-H]-functionalization of α,β-ynones was also uncovered. The mechanisms governing these processes have been thoroughly elucidated.

Full text of DOI:10.1021/acscatal.8b00397

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Letter
An Organophosphine-Catalyzed Intramolecular
Hydroacylation of Activated Alkynes
Atanu Mondal, Raju Hazra, Jagdeep Grover, Moluguri Raghu, and S. S. V. Ramasastry
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00397 • Publication Date (Web): 23 Feb 2018
Downloaded from http://pubs.acs.org on February 23, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street
N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
An OrganophosphineꢀCatalyzed Intramolecular Hydroacylation of
Activated Alkynes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Atanu Mondal, Raju Hazra, Jagdeep Grover, Moluguri Raghu and S. S. V. Ramasastry*
Organic Synthesis and Catalysis Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Sector 81, S A S Nagar, Manauli PO, Punjab 140 306, India
Supporting Information
Whereas activated alkenes are the usual substrates in the
ABSTRACT: We present the details of an organophosphineꢀ
MBH reaction, we are inquisitive about the fate of activated alꢀ
kynes under the typical MBH set up. This proposition is indeed
pursued with activated alkynes during the development of halo
aldol reactions3 and chalcogenoꢀMBH reactions,4 which are typiꢀ
cally mediated by metalꢀbased Lewis acids (Scheme 1b). In his
seminal report on the chalcogenoꢀMBH reaction,4a Kataoka menꢀ
tions that ‘the BaylisꢀHillman reaction of active alkynes with alꢀ
dehydes cannot proceed from the mechanistic viewpoint of the
reaction’. Herein, we report an organocatalytic intramolecular
MBHꢀtype reaction of α,βꢀynones that provides straightforward
access to 1,3ꢀcyclopentaꢀ, cycloheptaꢀ and cyclooctadioneꢀfused
arenes and heteroarenes without the need to employ any external
agents other than a nucleophilic trigger (Lewis base) in catalytic
amounts (Scheme 1c). The overall transformation also represents
an organophosphineꢀcatalyzed hydroacylation of α,βꢀynones. So
far, the hydroacylation of unactivated and activated alkynes is
known to be facilitated by either transition metal complexes5 or Nꢀ
heterocyclic carbenes (NHCs) (Scheme 1d).6
catalyzed MoritaꢀBaylisꢀHillmanꢀtype reaction of activated alꢀ
kynes. The outcome is an intramolecular hydroacylation of α,βꢀ
ynones leading to the formation of 1,3ꢀcyclopentaꢀ, cycloheptaꢀ
and cyclooctadioneꢀfused arenes and heteroarenes. In addition,
during the course of the investigation, a phosphineꢀcatalyzed inꢀ
tramolecular aldol reaction of ketoꢀynones via δ’[C(sp3)ꢀH]ꢀ
functionalization was discovered, and a new annulation event
comprising of a ω’[C(sp3)ꢀH]ꢀfunctionalization of α,βꢀynones
was also uncovered. The mechanisms governing these processes
have been thoroughly elucidated.
KEYWORDS: hydroacylation, organophosphine, ynones, Moritaꢀ
BaylisꢀHillman reaction, cyclopentanes, heterocycles, annulation
The MoritaꢀBaylisꢀHillman (MBH) reaction is a versatile CꢀC
bondꢀforming reaction between an activated alkene and a carbon
electrophile, commonly facilitated by a nucleophilic catalyst
(Scheme 1a).1 This reaction attracted the attention of synthetic
chemists owing to its adaptability, operational simplicity, and
being atomꢀeconomic and organocatalytic. Our own efforts in this
field provided new approaches for the synthesis of an array of
cyclopenta[b]annulated arenes and heteroarenes.2
The envisioned reaction was studied on the model substrate
1a,7 wherein the α,βꢀynone and aldehyde functionalities were
tethered ortho to each other (Scheme 2). To our surprise, the reacꢀ
tion of 1a in the presence of 10 mol% of PCy3 at room temperaꢀ
ture furnished an unexpected product 2a8 in 78% yield.
Scheme 2. An Unexpected Outcome of the MBHꢀType
Reaction of the Ynone 1a.
Scheme 1. Background and Significance of this Work.1ꢀ6
a) General representation of the Morita-Baylis-Hillman (MBH) reaction
O
O
Y
Z
PCy3 (10 mol%)
R1
R3N or R3P
R1
R2
R3
Ph
Ph
CH2Cl2, 6 h, rt
78%
R2
X = Electronꢀwithdrawing group
Y = O, NPg; Z = OH, NHPg
CHO
1a
O
X
X
2a
R3
Represents an organocatalytic hydroacyative cyclopentannulation
b) Halo aldol and chalcogeno-MBH reactions of activated alkynes
α,β-ynones
Y
O
H
Z
Some of the noteworthy features associated with the converꢀ
sion of 1a to 2a are: i) the present method constitutes a metalꢀfree
(and organocatalytic) alternative for the intramolecular hydroacꢀ
ylation of ynones. In this context, it is worth noting that α,βꢀ
ynones are rarely employed as substrates in a hydroacylation proꢀ
cess,9 which is indeed a limitation of the existing methods, ii) it
also exemplifies an unusual entry for the construction of densely
functionalized indanes. The persistent and widespread occurrence
of several bioactive natural products possessing indane framework
can make this an attractive strategy.10
H
MLn/activator
R1
O
M = metal; L = halide
L
R1
c) Organophosphine-catalyzed hydroacylation of α,β-ynones: This work
O
O
R1
H
PR3 (cat.)
R1
O
O
d) Known so far: Metal- or NHC-catalyzed hydroacylation of alkynes
Having realized the significance of the aforementioned obserꢀ
vation, we commenced to optimize the reaction conditions (Table
1). During the evaluation of phosphines, a marked improvement
in the yield of 2a was observed with PPh3 (entry 4). A subsequent
solvent screening with PPh3 as the catalyst did not offer any furꢀ
O
O
O
R1
(or)
R1
[M] or [NHC]
R1
H
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 6
ther improvements (entries 5ꢀ10). The feasibility of performing
Thus, 10 mol% of the cheap and readily available PPh3 was
identified as the catalyst for the conversion of 1a to 2a. To underꢀ
stand the scope and generality of this process, we applied the
optimized conditions to substrates bearing different electronic
features. The results are summarized in Table 2. A wide range of
2ꢀalkylidine and 2ꢀarylidineꢀ1,3ꢀindanediones possessing both
electron donating as well as electron withdrawing groups could be
conveniently assembled in 67ꢀ91% yield range (Table 2, 2bꢀl).
The reaction in brine was realized to be marginally less yielding
compared to the respective reaction in DCM (2c,d,i,j), which
could be attributed to the miscibility issues. The ynones with alkyl
groups also conveniently furnished the respective indanediones in
good yields (2g,h). Apart from ynones, enynoneꢀbearing subꢀ
strates were also demonstrated to be efficient under the optimized
conditions. For example, 2l and 2m were obtained in 72% and
67% yields, respectively. The generality of this method is furꢀ
thered with the synthesis of functionalized 1,3ꢀcyclopentadioneꢀ
fused benzothiophenes (2n) and benzofurans (2m,o,p) in good to
excellent yields.
the reaction under aqueous conditions was also verified. Interestꢀ
ingly, the reaction generated 2a in 88% yield even in the presence
of water (entry 9).2c,11 Indeed, the best yield of the product (93%)
was realized when brine solution was employed as the solvent
(entry 10).
1
2
3
4
5
6
7
8
Table 1. Optimization of the Reaction Parametersa
O
O
catalyst (10 mol%)
solvent, rt
Ph
Ph
9
CHO
O
1a
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yield
entry catalyst (10 mol%)
solvent
t (h)
(%)b
1
2
3
PCy3
PMe2Ph
PEtPh2
PPh3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
toluene
6
8
4
5
3
12
4
72
40
8
78
48
72
92
76
82
70
79
88
93
ꢀ
4
5
PPh3
6
PPh3
With the advent of the successful hydroacylative pentannulaꢀ
tion reaction, we intended to extend this concept to a new subꢀ
strate design 3 (Table 3). It was anticipated that the phoshineꢀ
promoted reaction of the biarylꢀynone 3 could provide 4.12 Indeed,
gratifyingly, 3a under the prototypical conditions described in
Table 2 delivered the desired product 4a in 54% yield. This result
represents the first assemblage of fused sevenꢀmembered carboꢀ
cycles via an intramolecular hydroacylation of α,βꢀynones.12
Through a brief optimization,13 the yield of 4a could be improved
to 86% with PCy3 as the catalyst in toluene.
7
PPh3
CH3OtBu
2ꢀMeꢀTHF
waterꢀTHF
brine
CH2Cl2
CH2Cl2
8
PPh3
9
PPh3
10
11
12
PPh3
DABCO
βꢀICD
48
12
ꢀ
aReaction conditions: A mixture of 1a (0.1 mmol) and a catalyst (0.01
mmol) in a solvent (1 mL) was stirred at room temperature until 1a disapꢀ
peared (by TLC). bChromatographic yields.
Table 3. Substrate Scope: Dibenzo[a,c]cycloheptanedionesa,b,c
On the other hand, nitrogenꢀcentred Lewis bases such as 1,4ꢀ
diazabicyclo[2.2.2]octane (DABCO) and βꢀisocupreidine (βꢀ
ICD), which are some of the most successful catalysts in the Bayꢀ
lisꢀHillman chemistry, failed to generate even traces of the exꢀ
pected product (Table 1, entries 11ꢀ12).
R1
O
R2
R2
PCy3 (10 mol%)
toluene, 40 oC
OHC
O
R3
R1
R3
O
3
4
Table 2. Substrate Scope: Cyclopentannulated Arenes and
Heteroarenesa,b,c
4a, R = Ph, 48 h, 54%d
4a, R = Ph, 7 h, 86%
4b, R = (pꢀPh)C6H4, 7 h, 75%
4c, R = 1ꢀnaphthyl, 8 h, 74%
4d, R = mꢀtolyl, 8 h, 86%e
4e, R = [m,pꢀ(OMe)2]C6H3, 8 h, 78%
4f, R = cyclopropyl, 7 h, 82%
O
O
4d
R
OMe
F
MeO
O
O
O
O
O
Ph
Ph
MeO
O
R
OMe
R
4i, R = H, 8 h, 86% (5:1)
4j, R = OMe, 8 h 72%
4g, 7 h, 83% (1:1)
4h, 7 h, 80% (5:1)
O
O
O
Ph
Ph
O
O
O
Ph
4k, 18 h, 74% (5:1)e
4l, 36 h, 68% (3:1)
4m, 36 h, 73% (2:1)
aReaction conditions: A mixture of 3 (0.1 mmol) and PCy3 (0.01 mmol) in
o
b
toluene (1 mL) was stirred at 40 C until 3 disappeared (by TLC). Chroꢀ
matographic yields. cE/Z ratio in the parenthesis is that of the purified
sample; crude E/Z is 1:1. dWith PPh3 (10 mol%) in DCM at room temperaꢀ
e
e
ture. 40 mol% PCy3 was employed. Xꢀray crystal structure of 4d was
obtained (CCDC 1584071), see the Supporting Information for details.
aReaction conditions: A mixture of 1 (0.1 mmol) and PPh3 (0.01 mmol) in
DCM (1 mL) was stirred at room temperature until 1 disappeared (by
An evaluation of the substrate scope under the optimized conꢀ
ditions provided an array of 2ꢀarylidene and 2ꢀalkylidene dibenꢀ
zo[a,c]cycloheptadiones possessing diverse electronic characters
c
TLC). bChromatographic yields. 2i, 2j, 2mꢀp were obtained in 1:1 E/Z
ratio. dOutcome in brine medium. eAt 40 oC.
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
in 68ꢀ86% yield (Table 3, 4bꢀm). In general, consistent turnaꢀ
round times and excellent yields were achieved, thereby highlightꢀ
ing the generality of the method. The presence of electronꢀ
donating groups either on the alkyne (4e) or on the aryl backbone
(4hꢀj) displayed only a minor influence on the efficiency of the
reaction. Further, enynones also generated the respective products
in good yield. For example, 4k was obtained in 74% yield. On the
other hand, longer reaction times during the formation of 4l and
4m could be attributed to the restricted rotation across the arylꢀ
aryl bond.
1
2
3
4
5
6
7
8
9
Next, we turned our attention to gain insights about the mechꢀ
anism of the phosphineꢀcatalyzed hydroacylation process
(Scheme 3). Towards this, the substrate 1nD possessing deuteratꢀ
ed aldehyde functionality (95%D) was subjected to the optimized
conditions (Scheme 3a). Interestingly, the extent of ‘D’ꢀ
incorporation in the product 2nD went down to 30%, indicating
that the transformation of 1nD to 2nD at a certain stage may be
involving a competing intermolecular protonation pathway, in
addition to an intramolecular proton transfer. The hypothesized
proton exchange with the solvent environment was further eviꢀ
denced when 1a was treated in the presence of deuterated solvents
(Scheme 3b) where the ‘D’ꢀincorporation in the product 2aD was
identified to be 70% in THFꢀD2O mixture, and 76% in THFꢀ
CD3OD; but not 100%.
Having realized the crucial role of the aldehydic proton in faꢀ
cilitating the reaction, it was anticipated that its replacement with
an alkyl group may provide further insights about the reaction
mechanism. In addition, it was also envisioned that the alkyl
shifts, analogous to hydride and proton shifts, may lead to the
formation of unexpected products. Based on these considerations,
when 5a was subjected under the reaction conditions described in
Table 2, an unexpected product 6a was isolated in 43% yield (Taꢀ
ble 4). Through an optimization of different parameters,13 the
yield of 6a could be improved to 87%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Substrate Scope: 3ꢀEthynylꢀ3ꢀhydroxyindanonesa,b
A deuterium scrambling experiment between 1a and 1nD was
also conducted (Scheme 3c). Realization of the products 2aD and
2nD with 10% and 25% ‘D’ꢀincorporation, respectively, suggests
that the aldehydic proton is lost to the solvent environment during
the transformation, and due to the intermolecularity of the proton
transfer step, it reꢀenters the system (10%D in 2aD).
Scheme 3. Mechanistic Studies
O
O
Ph
D
~30%
Ph
PPh3 (10 mol%)
D
(a)
CH2Cl2, rt
9 h, 90%
~95%
S
S
O
O
2nD (E/Z = 1:1)
1nD
O
PPh3 (10 mol%)
D
1a
(b)
(c)
in THFꢀD2O (1:1): 42 h, 81%, ~70%D
in THFꢀCD3OD (1:1): 11 h, 80%, ~76%D
Ph
O
2aD
PPh3 (10 mol%)
1nD
(~95%D)
2aD
2nD
+
1a
+
(44%, ~10%D)
(42%, ~25%D)
CH2Cl2, rt, 9 h
Based on the experimental evidence, a plausible mechanism is
proposed in Scheme 4. Initial phosphaꢀMichael addition followed
by an intramolecular aldol reaction, which are typical of the MBH
reaction, provides the zwitterionic species 1a1. The αꢀproton to
alkoxide in 1a1 is acidic enough to undergo an intermolecular
proton transfer (presumably assisted by adventitious water) to
form the vinylogous ylide 1a2. The ylide 1a3 (in resonance with
1a2) upon further proton transfer converts to the enol 1a4, which
upon elimination of phosphine generates 2a. The mechanism of
formation of 4 from 3 can also be explained in an analogous manꢀ
ner.
The ylide 1a314 is believed to be responsible for the H/D abꢀ
straction from the solvent, which is in line with the experimental
observations. Further, the lack of stereoselectivity in products
could be due to the free rotation across the C2ꢀC1’ bond in 1a3 or
1a4.15
aReaction conditions: A mixture of 5 (0.1 mmol) and PBu3 (0.02 mmol) in
tertꢀbutanol (1 mL) was stirred at room temperature until 5 disappeared
(by TLC). bIsolated yields after column chromatography. cPPh3 (10 mol%)
in DCM at rt.
Subsequent evaluation of a variety of substrates under the opꢀ
timized conditions provided access to a series of 3ꢀethynylꢀ3ꢀ
hydroxyindanones (6bꢀf) in 68ꢀ88% yield range. Furthermore, the
heteroareneꢀfused 3ꢀethynylꢀ3ꢀhydroxycyclopentanones (6g,h)
could also be readily synthesized by this method, which would
otherwise require a sequence of multiꢀstep synthetic reactions. As
a significant extension of this methodology, the δ’ꢀbranched subꢀ
strate 5i (when R1 = Me, R2 = Ph) formed 6i containing two conꢀ
tiguous stereogenic centres in 72% yield, while 5j (when R1 = R2
= Ph) generated straightaway the ynenone 7j in 80% yield, apparꢀ
ently via the in situ dehydration of the respective βꢀhydroxy keꢀ
tones (6j).
Scheme 4. Plausible Mechanism
The mechanism of the formation of 6 from 5 is depicted in
Table 4. Michael addition of the phosphine to 5 followed by the
δ’ꢀproton abstraction of the zwitterion 5’ generates the enolate
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
5’’. Intramolecular aldol reaction of 5’’ and an interꢀ or intramoꢀ
lecular vinylic proton abstraction by the alkoxide provides 6.16
for the synthesis of bioactive natural products are underway. The
results will be communicated in due course.
A
1
striking feature of this transformation is that it involves an unꢀ
precedented organocatalytic δ’[C(sp3)ꢀH]ꢀfunctionalization of
α,βꢀynones.17 To the extent of our knowledge, this study also
demonstrates a phoshineꢀcatalyzed intramolecular aldol reaction
of ketoꢀynones.18
2
3
4
5
6
7
8
9
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.xxxxx.
Experimental details and characterization data for all
new compounds (1H NMR, 13C NMR) (PDF)
Xꢀray crystal structure of 4d (CIF)
Further, in analogy to the concept described in Table 4, it was
anticipated that the biarylꢀynone 8a would produce 9a (Table 5).
However, the reaction of 8a under the optimized conditions furꢀ
nished the dibenzo[a,c]cyclooctadione 10a in 67% yield. Since
such a transformation is without precedence, few other analogs
(10bꢀe) were synthesized in good yields (65ꢀ78%).19 Regarding
the mechanism, it can be postulated that the zwitterionic species
8a1 abstracts the ω’ꢀproton to afford the enolate 8a2. Rather than
undergoing an aldol reaction, the enolate 8a2 cyclizes to generate
the ylide 8a3. An eventual 1,2ꢀproton shift followed by the elimiꢀ
nation of phosphine yields 10a. The PꢀO interaction depicted in
8a1 or 8a2 is considered responsible for the formation of Eꢀ
selective products. In addition to providing access to several bioꢀ
active natural products possessing dibenzo[a,c]cyclooctane core,20
this method also exemplifies an organocatalyzed ω’[C(sp3ꢀH)]ꢀ
functionalization of ynones.
Xꢀray crystal structure of 10b (CIF)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ramsastry@iisermohali.ac.in
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
IISER Mohali is acknowledged for funding, and for the NMR,
mass, and departmental Xꢀray facilities. A.M., R.H., J.G., and
M.R. thank IISER Mohali for research fellowships.
Table 5. Substrate Scope: Dibenzo[a,c]cyclooctanedionesa,b
Ph
O
OH
Ph
O
REFERENCES
8
7
PCy3 (20 mol%)
tBuOH, 7 h, rt
O
Ph
(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. A Tertiary Phosphineꢀ
catalyzed Reaction of Acrylic Compounds with Aldehydes. Bull. Chem.
Soc. Jpn. 1968, 41, 2815ꢀ2815. (b) Baylis, A. B.; Hillman, M. E. D.
German Patent 2155113, 1972 [Chem. Abstr. 1972, 77, 34174q]. (c)
Masson, G.; Housseman, C.; Zhu, J. The Enantioselective Morita–
Baylis–Hillman Reactionand Its Aza Counterpart. Angew. Chem., Int.
Ed. 2007, 46, 4614ꢀ4628. (d) Singh, V.; Batra, S. Advances in the Bayꢀ
lis–Hillman Reactionꢀassisted Synthesis of Cyclic Frameworks. Tetraꢀ
hedron 2008, 64, 4511ꢀ4574. (e) Declerck, V.; Martinez, J.; Lamaty, F.
AzaꢀBaylis−Hillman Reaction. Chem. Rev. 2009, 109, 1ꢀ48. (f) Basaꢀ
vaiah, D.; Reddy, B. S.; Badsara, S. S. Recent Contributions from the
Baylis−Hillman Reaction to Organic Chemistry. Chem. Rev. 2010, 110,
5447ꢀ5674. (g) Wei, Y.; Shi, M. Multifunctional Chiral Phosphine Orꢀ
ganocatalysts in Catalytic Asymmetric Morita−Baylis−Hillman and Reꢀ
lated Reactions. Acc. Chem. Res. 2010, 43, 1005ꢀ1018. (h) Mansilla, J.;
Saá, J. M. Enantioselective, Organocatalytic MoritaꢀBaylisꢀHillman and
AzaꢀMoritaꢀBaylisꢀHillman Reactions: Stereochemical Issues. Moleꢀ
cules 2010, 15, 709ꢀ734. (i) Basavaiah, D.; Veeraraghavaiah, G. The
Baylis–Hillman Reaction: A Novel Concept for Creativity in Chemistry.
Chem. Soc. Rev. 2012, 41, 68ꢀ78. (j) Wei, Y.; Shi, M. Recent Advances
in Organocatalytic Asymmetric Morita–Baylis–Hillman/azaꢀMorita–
Baylis–Hillman Reactions. Chem. Rev. 2013, 113, 6659ꢀ6690. (k) Fan,
Y. C.; Kwon, O. Advances in Nucleophilic Phosphine Catalysis of Alꢀ
kenes, Allenes, Alkynes, and MBHADs. Chem. Commun. 2013, 49,
11588ꢀ11619. (l) Bharadwaj, K. C. Intramolecular Morita–Baylis–
Hillman and Rauhut–Currier reactions. A Catalytic and Atom Economic
Route for Carbocycles and Heterocycles. RSC Adv. 2015, 5, 75923ꢀ
75946.
(2) (a) Satpathi, B.; Ramasastry, S. S. V. Morita–Baylis–Hillman Reacꢀ
tion of β,βꢀDisubstituted Enones: An Enantioselective Organocatalytic
Approach for the Synthesis of Cyclopenta[b]annulated Arenes and Hetꢀ
eroarenes. Angew. Chem., Int. Ed. 2016, 55, 1777ꢀ1781. (b) Satpathi, B.;
Ramasastry, S. S. V. Enantioselective Organocatalytic Intramolecular
Morita–Baylis–Hillman Reaction of Some Unusual Substrates. Synlett
2016, 27, 2178ꢀ2182. (c) Raghu, M.; Grover, J.; Ramasastry, S. S. V.
Cyclopenta[b]annulation of Heteroarenes by Organocatalytic
γ′[C(sp3)−H] Functionalization of Ynones. Chem.ꢀEur. J. 2016, 22,
18316ꢀ18321. (d) Satpathi, B.; Wagulde, S. V.; Ramasastry, S. S. V. An
Enantioselective Organocatalytic Intramolecular Morita–Baylis–
Hillman (IMBH) Reaction of Dienones, and Elaboration of the IMBH
Adducts to Fluorenones. Chem. Commun. 2017, 53, 8042ꢀ8045.
O
O
9a
8a
10a, 67%
(expected in analogy,
but not formed)
(observed product)
PR3
O
O
O
PR3
PR3
PR3
Ph
Ph
Ph
ω’
8a1
8a2
8a3
O
O
O
F
O
O
O
R
Ph
Ph
O
O
10b, R = 1ꢀnaphtyl, 7 h, 78%c
10c, R = mꢀtolyl, 7 h, 65%
O
10d, 5 h, 66%
10e, 5 h, 70%
ORTEP diagram of 10b
aReaction conditions: A mixture of 8 (0.1 mmol) and PCy3 (0.02 mmol) in
tertꢀbutanol (1 mL) was stirred at room temperature until 8 disappeared
(by TLC). bIsolated yields after column chromatography. cXꢀray crystal
structure of 10b was obtained (CCDC 1814310), see the Supporting Inꢀ
formation for details.
In conclusion, we presented an unprecedented case of the
MBHꢀtype reaction of α,βꢀynones, which provides access to a
variety of cyclopentaꢀ and cycloheptaꢀfused arenes and hetꢀ
eroarenes. Further, serendipitous organocatalytic approaches for
the synthesis of 3ꢀethynylꢀ3ꢀhydroxyindanones involving
a
δ’[C(sp3)ꢀH]ꢀfunctionalization, and dibenzo[a,c]cyclooctadiones
via ω’[C(sp3)ꢀH]ꢀfunctionalization of α,βꢀynones have also been
described. Intriguing mechanistic details governing these processꢀ
es were elucidated. Efforts to apply the methods described herein
(3) Few selected articles on this topic, see: (a) Li, G.; Xu, X.; Chen, D.;
Timmons, C.; Carducci, M. D.; Headley, A. D. Asymmetric Halo Aldol
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
Reaction (AHA). Org. Lett. 2003, 5, 329ꢀ331. (b) Senapati, B. K.;
Hwang, G.ꢀS.; Lee, S.; Ryu, D. H. Enantioselective Synthesis of βꢀIodo
Morita–Baylis–Hillman Esters by Catalytic Asymmetric Threeꢀ
Relay Catalysis: Divergent Synthesis of Furo[3,4ꢀb]indoles and Cycloꢀ
penta[b]indoles from 3ꢀ(2ꢀAminophenyl)ꢀ1,4ꢀenynols. Org. Biomol.
Chem. 2016, 14, 5563ꢀ5568 and references cited therein.
1
2
a
Component Coupling Reaction. Angew. Chem., Int. Ed. 2009, 48, 4398ꢀ
4401. (c) Hachiya, I.; Ito, S.; Kayaki, S.; Shimizu, M. Diastereoselective
Iodoaldol Reaction of γꢀAlkoxyꢀα,βꢀAlkynyl Ketone Derivatives Proꢀ
moted by Titanium Tetraiodide. Asian J. Org. Chem. 2013, 2, 931ꢀ934.
(4) For a seminal contribution, see: (a) Kataoka, T.; Kinoshita, H.; Kiꢀ
noshita, S.; Iwamura, T.; Watanabe, S.ꢀI. A Convenient Synthesis of αꢀ
Halomethylene Aldols or βꢀHaloꢀαꢀ(hydroxyalkyl)acrylates Using the
ChalcogenoꢀBaylis–Hillman Reaction. Angew. Chem., Int. Ed. 2000, 39,
2358ꢀ2360. Recent reviews on this topic, see: (b) McGarrigle, E. M.;
Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K.
Chalcogenides as Organocatalysts. Chem. Rev. 2007, 107, 5841ꢀ5883.
(c) Cież, D.; Pałasz, A.; Trzewik, B. Titanium Enolate Chemistry at the
Beginning of the 21st Century. Eur. J. Org. Chem. 2016, 1476ꢀ1493.
(5) (a) Sakai, K.; Ide, J.; Oda, O.; Nakamura, N. Synthetic Studies on
Prostanoids 1 Synthesis of Methyl 9ꢀoxoprostanoate. Tetrahedron Lett.
1972, 13, 1287ꢀ1290. (b) Tanaka, K.; Fu, G. C. A Versatile New Methꢀ
od for the Synthesis of Cyclopentenones via an Unusual Rhodiumꢀ
Catalyzed Intramolecular Trans Hydroacylation of an Alkyne. J. Am.
Chem. Soc. 2001, 123, 11492ꢀ11493. (c) Takeishi, K.; Sugishima, K.;
Sasaki, K.; Tanaka, K. RhodiumꢀCatalyzed Intramolecular Hydroacylaꢀ
tion of 5ꢀ and 6ꢀAlkynals: Convenient Synthesis of αꢀ
Alkylidenecycloalkanones and Cycloalkenones. Chem.ꢀEur. J. 2004, 10,
5681ꢀ5688. (d) Tanaka, K.; Sasaki, K.; Takeishi, K.; Hirano, M. Cationꢀ
ic P(OPh)3ꢀ or PPh3ꢀRhodium(I) ComplexꢀCatalyzed Isomerizations of
5ꢀAlkynals to δꢀAlkynyl Ketones, Cyclopentꢀ1ꢀenyl Ketones, and Cyꢀ
clohexenones. Eur. J. Org. Chem. 2007, 5675ꢀ5685. (e) Jun, C.ꢀH.; Jo,
EꢀA.; Park, J.ꢀW. Eur. J. Org. Chem. 2007, 1869ꢀ1881. (f) Willis, M. C.
Chem. Rev. 2010, 110, 725ꢀ748. (g) GonzalezꢀRodriguez, C.; Pawley,
R. J.; Chaplin, A. B.; Thompson, A. L.; Weller, A. S.; Willis, M. C.
(11) Waterꢀpromoted phosphineꢀcatalyzed reactions are not uncommon.
For some selected works, see: (a) Methot, J. L.; Roush, W. R. Synthetic
Studies toward FR182877. Remarkable Solvent Effect in the Vinyloꢀ
gous Morita−Baylis−Hillman Cyclization. Org. Lett. 2003, 5, 4223ꢀ
4226. (b) Stewart, I. C.; Bergman, R. G.; Toste, F. D. Phosphineꢀ
Catalyzed Hydration and Hydroalkoxylation of Activated Olefins:ꢁ Use
of a Strong Nucleophile to Generate a Strong Base. J. Am. Chem. Soc.
2003, 125, 8696ꢀ8697. (c) GonzalezꢀCruz, D.; Tejedor, D.; de Armas,
P.; GarciaꢀTellado, F. Dual Reactivity Pattern of Allenolates “On Waꢀ
ter”: The Chemical Basis for Efficient AllenolateꢀDriven Organocatalytꢀ
ic Systems. Chem. ꢀEur. J. 2007, 13, 4823ꢀ4832. (d) Xia, Y.; Liang, Y.;
Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu, Z.ꢀX. An
Unexpected Role of a Trace Amount of Water in Catalyzing Proton
Transfer in PhosphineꢀCatalyzed (3 + 2) Cycloaddition of Allenoates
and Alkenes. J. Am. Chem. Soc. 2007, 129, 3470ꢀ3471. (e) Mercier, E.;
Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Phosphine Triggered
[3+2] Allenoate–Acrylate Annulation: A Mechanistic Enlightenment.
Tetrahedron Lett. 2007, 48, 3617ꢀ3620. (f) Jiang, Y.ꢀQ.; Shi, Y.ꢀL.; Shi,
M. Chiral PhosphineꢀCatalyzed Enantioselective Construction of γꢀ
Butenolides Through Substitution of Morita−Baylis−Hillman Acetates
with 2ꢀTrimethylsilyloxy Furan. J. Am. Chem. Soc. 2008, 130, 7202ꢀ
7203. (g) Fang, Y.ꢀQ.; Jacobsen, E. N. Cooperative, Highly Enantioseꢀ
lective Phosphinothiourea Catalysis of Imine−Allene [3 + 2] Cycloaddiꢀ
tions. J. Am. Chem. Soc. 2008, 130, 5660ꢀ5661.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) In the context of metalꢀcatalyzed hydroacylation reactions, Willis
opines that the intramolecular reactions to generate rings other than
fiveꢀmembered systems are not trivial, see Refꢀ5f.
(13) See the Supporting Information for the optimization studies.
(14) Efforts to trap 1a2 by a Wittig reaction were unsuccessful.
(15) This is unlike the typical intramolecular MBH reaction, which is Eꢀ
selective due to the favorable PꢀꢀO interaction, see Refꢀ2.
RhodiumꢀCatalyzed BranchedꢀSelective Alkyne Hydroacylation:
A
LigandꢀControlled Regioselectivity Switch. Angew. Chem., Int. Ed.
2011, 50, 5134ꢀ5138. (h) Yang, F.; Jin, T.; Yamamoto, Y. Synthesis of
2,3ꢀDihydroꢀ1HꢀIndenꢀ1ꢀOne Derivatives via NiꢀCatalyzed Intramolecꢀ
ular Hydroacylation. Tetrahedron 2012, 68, 5223ꢀ5228. (i) Oonishi, Y.
Development of Novel Cyclizations via Rhodacycle Intermediate and
Its Application to Synthetic Organic Chemistry. Chem. Pharm. Bull.
2015, 63, 397ꢀ407. (j) Ghosh, A.; Johnson, K. F.; Vickerman, K. L.;
Walker, J. A.; Stanley, L. M. Recent Advances in Transition Metalꢀ
Catalysed Hydroacylation of Alkenes and Alkynes. Org. Chem. Front.
2016, 3, 639ꢀ644.
(6) (a) Biju, A. T.; Wurz, N. E.; Glorius, F. NꢀHeterocyclic Carbeneꢀ
Catalyzed Cascade Reaction Involving the Hydroacylation of Unactiꢀ
vated Alkynes. J. Am. Chem. Soc. 2010, 132, 5970ꢀ5971. (b) Veꢀ
dachalam, S.; Wong, Q.ꢀL.; Maji, B.; Zeng, J.; Ma, J.; Liu, X.–W. Nꢀ
Heterocyclic Carbene Catalyzed Intramolecular Hydroacylation of Acꢀ
tivated Alkynes: Synthesis of Chromones. Adv. Synth. Catal. 2011, 353,
219ꢀ225. (c) Wang, Z.; Yu, Z.; Wang, Y.; Shi, D. NꢀHeterocyclic Carꢀ
bene Catalyzed Intramolecular Hydroacylation of Alkynylphosphonates.
Synthesis 2012, 44, 1559ꢀ1568. (d) Yetra, S. R.; Patra, A.; Biju, A. T.
Recent Advances in the NꢀHeterocyclic Carbene (NHC)ꢀ
Organocatalyzed Stetter Reaction and Related Chemistry. Synthesis
2015, 47, 1357ꢀ1378.
(7) (a) Asahina, K.; Matsuoka, S.; Nakayama, R.; Hamura, T. An Effiꢀ
cient Synthetic Route to 1,3ꢀbis(arylethynyl)isobenzofuran Using
Alkoxybenzocyclobutenone as a Reactive Platform. Org. Biomol. Chem.
2014, 12, 9773ꢀ9776. (b) Zhang, Y.; Guo, D.; Ye, S.; Liu, Z.; Zhu, G.
Synthesis of Trifluoromethylated Naphthoquinones via Copperꢀ
Catalyzed Cascade Trifluoromethylation/Cyclization of 2ꢀ(3ꢀ
Arylpropioloyl)benzaldehydes. Org. Lett. 2017, 19, 1302ꢀ1305.
(8) Li, Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.; Pan, S. C−H Bond
Oxidation Initiated Pummererꢀ and KnoevenagelꢀType Reactions of
Benzyl Sulfide and 1,3ꢀDicarbonyl Compounds. Org. Lett. 2008, 10,
803ꢀ805.
(9) (a) Willis, M. C.; RandellꢀSly, H. E.; Woodward, R. L.; McNally, S.
J.; Currie, G. S. RhodiumꢀCatalyzed Intermolecular Chelation Conꢀ
trolled Alkene and Alkyne Hydroacylation:ꢁ Synthetic Scope of βꢀSꢀ
Substituted Aldehyde Substrates. J. Org. Chem. 2006, 71, 5291ꢀ5297.
(b) Khong, S.; Kwon, O. PhosphineꢀInitiated GeneralꢀBaseꢀCatalyzed
Quinolone Synthesis. Asian J. Org. Chem. 2014, 3, 453ꢀ457.
(16) Alternatively, a catalytic amount of tertꢀbutoxide generated in situ
may also deprotonate the vinylic proton in 5’’’.
(17) For our earlier work on a phosphineꢀcatalyzed
functionalization of ꢀynones, see Refꢀ2c.
γ
’[C(sp3)ꢀH]ꢀ
α,β
(18) For a phosphineꢀcatalyzed Mukaiyama aldol reaction, see: (a)
Matsukawa, S.; Fukazawa, K.; Kimura, J. PolymerꢀSupported PPh3 as a
Reusable Organocatalyst for the Mukaiyama Aldol and Mannich Reacꢀ
tion. RSC Adv. 2014, 4, 27780ꢀ27786. For a phosphine catalyzed niꢀ
troaldol reaction, see: (b) Weeden, J. A.; Chisholm, J. D. Phosphineꢀ
Catalyzed Nitroaldol Reactions. Tetrahedron Lett. 2006, 47, 9313ꢀ9316.
For an aldol reaction triggered by a RauhutꢀCurrier reaction, see: (c)
Thalji, R. K.; Roush, W. R. Remarkable PhosphineꢀEffect on the Intraꢀ
molecular Aldol Reactions of Unsaturated 1,5ꢀDiketones:ꢁ Highly Regiꢀ
oselective Synthesis of CrossꢀConjugated Dienones. J. Am. Chem. Soc.
2005, 127, 16778ꢀ16779.
(19) The construction of mediumꢀsized carbocycles is a challenge in orꢀ
ganic synthesis, see: (a) Winnik, M. A. Cyclization and the Conforꢀ
mation of Hydrocarbon Chains. Chem. Rev. 1981, 81, 491ꢀ524. (b) Meꢀ
hta, G.; Singh, V. Progress in the Construction of Cyclooctanoid Sysꢀ
tems:ꢁ New Approaches and Applications to Natural Product Syntheses.
Chem. Rev. 1999, 99, 881ꢀ930.
(20) (a) Tan, R.; Li, L.; Fang, Q. The Stereostructure of Wuweizisu B.
Planta Medica 1986, 52, 49ꢀ51. (b) Liu, J.ꢀS.; Li, L. Schisantherins P
and Q, Two Lignans from Kadsura Coccinea. Phytochemistry 1995, 38,
1009ꢀ1011. (c) Monovich, L. G.; Le Huerou, Y.; Roenn, M.; Molander,
G. A. Total Synthesis of (−)ꢀSteganone Utilizing a Samarium(II) Iodide
Promoted 8ꢀEndo Ketyl−Olefin Cyclization. J. Am. Chem. Soc. 2000,
122, 52ꢀ57. (d) Beryozkina, T.; Appukkuttan, P.; Mont, N.; Van der
Eycken, E. MicrowaveꢀEnhanced Synthesis of New (−)ꢀSteganacin and
(−)ꢀSteganone Aza Analogues. Org. Lett. 2006, 8, 487ꢀ490. (e) Gong,
W.; Babu, T. V. R. Conformation and Reactivity in Dibenzocyclooctaꢀ
dienes (DBCOD). A General Approach to the Total Synthesis of Fully
Substituted DBCOD Lignans via Borostannylative Cyclization of α,ωꢀ
Diynes. Chem. Sci. 2013, 4, 3979ꢀ3985. (f) Iwai, T.; Okochi, H.; Ito, H.;
Sawamura, M. Construction of EightꢀMembered Carbocycles through
Gold Catalysis with AcetyleneꢀTethered Silyl Enol Ethers. Angew.
Chem., Int. Ed. 2013, 52, 4239ꢀ4242.
(10) (a) Gabriele, B.; Mancuso, R.; Veltri, L. Recent Advances in the
Synthesis of Indanes and Indenes. Chem.ꢀEur. J. 2016, 22, 5056ꢀ5094.
(b) Manisha.; Dhiman, S.; Mathew, J.; Ramasastry, S. S. V. OneꢀPot
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
1
2
3
For Table of Contents Only
4
5
6
7
O
* products of the MBHꢀtype reaction of α,βꢀynones
* intramolecular hydroacylation of α,βꢀynones
O
Ar
Ar/
HetꢀAr
and
7
5
R2
O
R2
O
Ar
O
PR3
8
9
R2
O
R1
R2
w
h
e
HO
n
R2
Ar
R 1
O
=
a
8
l
Ar/
HetꢀAr
k
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
y
5
and
l
* phosphineꢀcatalyzed aldol reaction
* organocatalytic δ’ꢀ and ω’[C(sp3)ꢀH]ꢀfunctionalizations
Ar
O
O
ACS Paragon Plus Environment