Letter

Cite This: Org. Lett. 2020, 22, 46−51 pubs.acs.org/OrgLett

Complementary C−H Functionalization Mode of

Benzoylacetonitriles: Computer-Augmented Study of a Regio- and
Stereoselective Synthesis of Functionalized Benzofulvenes
Xia Song,† Bao Nguyen Do Doan,‡ Xinying Zhang,† Richmond Lee,*,‡ and Xuesen Fan*,†
†
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals,
School of Environment, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007,
China
‡
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Science and Mathematics Cluster, Singapore University of Technology and Design, 8 Somapah Road, Singapore 487372
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*
S Supporting Information

ABSTRACT: A highly regio- and stereoselective synthesis of

functionalized benzofulvenes via Rh(III)-catalyzed cascade
reactions of benzoyl acetonitrile/methylsulfone/acetate with
propargyl alcohols is presented herein. Mechanistic modeling
performed with density functional theory (DFT) calculations
suggested that the hydroxyl group and CsOAc played
important roles in mediating the 5-membered ring cyclization
by forming a very thermodynamically stable Rh(III)
intermediate. Another remarkable feature of this trans-
formation is its excellent stereoselectivity in that only E-
isomers are obtained.

B enzofulvene derivatives play important roles in medicinal

chemistry1 and material science.2 Recent studies identified
a number of benzofulvene-containing natural products with
Scheme 1. Previously Reported Transformations and Our
Observation

remarkable biological and pharmaceutical potential.3 In

addition, functionalized benzofulvenes are also versatile
building blocks widely used among the synthetic community.4
Due to their importance, several methods for the preparation
of benzofulvene derivatives have been developed. Among
them, a common approach involves the radical-initiated or
metal-catalyzed annulation of 1,2-difunctionalized (alkenyl/
alkenyl, alkenyl/alkynyl, alkynyl/alkynyl) benzenes.5 In
addition, this class of compounds could also be prepared via
the transformation of indenones,1b,6 enynyl triazoles, cyclo-
propenes, diarylacetylenes, etc.7 While these reported methods
are generally reliable and efficient, there are shortcomings such
as multistep prefunctionalization of commercial starting
materials and production of mixtures of regio- and stereo-
isomers. coupling partners,10,11 we have explored the reaction of
In recent years, direct functionalization of inert C(sp2)−H benzoylacetonitriles with propargyl alcohols in order to obtain
bonds followed by an intramolecular annulation has become hydroxyalkyl-substituted naphthonitriles as synthetic inter-
more and more important in generating fused heterocycles or mediates for the preparation of naphtho[2,3-c]furanone
carbocycles as no preactivation of substrates is required.8 In derivatives (Scheme 1 (2)). However, instead of the intended
this regard, Wang et al. have demonstrated that Rh(III)- ortho-hydroxyalkyl naphthonitrile, a benzofulvene derivative
catalyzed oxidative annulation of benzoylacetonitrile with featuring an acrylonitrile moiety and a hydroxyalkyl unit was
internal alkynes gave substituted naphthonitriles by sequential obtained (Scheme 1 (3)). It is worthwhile noting that while
functionalization of C(sp2)−H and C(sp3)−H bonds (Scheme there are some reports on the coupling of aryl ketones with
1 (1)).9 Inspired by this pioneering work, and together with
our interest in Rh(III)-catalyzed inert C(sp2)−H bond Received: October 29, 2019
functionalization by using propargyl alcohols as versatile Published: December 23, 2019

© 2019 American Chemical Society 46 DOI: 10.1021/acs.orglett.9b03858

Org. Lett. 2020, 22, 46−51
Organic Letters Letter

simple internal alkynes to give benzofulvenes,12 these reactions gave 3a in 62%, 71%, or 68% yield, respectively (entries 15−
usually afford a mixture of two regioisomers from asymmetrical 17). Finally, a control experiment was performed to make sure
inner alkynes and two E/Z isomers from α-substituted aryl that Rh(III) catalyst is required for this reaction (entry 18).
ketones (Scheme 1 (4)). On the contrary, the reaction of With the optimal reaction conditions established, we focused
benzoylacetonitrile with propargyl alcohol led to the formation on screening the substrate scope. First, the suitability of various
of functionalized benzofulvene in a highly regio- and functional group substitutions in 1 was studied by using 2a as a
stereoselective manner as only one of the four theoretically model substrate. As shown in Scheme 2, molecules bearing a
possible stereo- and regioisomers was obtained. Therefore, we
were strongly motivated to develop this novel transformation Scheme 2. Substrate Scope for the Synthesis of 3 (I)a,b
into a general synthetic methodology toward benzofulvene
derivatives. In addition, we were also interested in making
efforts to understand the observed unique regio- and
stereoselectivity through computational modeling with density
functional theory (DFT). Herein, we report our detailed
studies in this regard.
When a mixture of 3-oxo-3-phenylpropanenitrile (1a) and 2-
methyl-4-phenylbut-3-yn-2-ol (2a) was subjected to
[RhCp*Cl2]2 catalyst and NaOAc in DCM at 60 °C, (E)-2-
(2-(2-hydroxypropan-2-yl)-3-phenyl-1H-inden-1-ylidene)-
acetonitrile (3a) was obtained in 24% yield (Table 1, entry 1),

Table 1. Optimization Study for the Formation of 3aa

entry additive solvent T (°C) yieldb (%)

1 NaOAc DCM 60 24
2 NaOAc DCE 60 29
3 NaOAc toluene 60 20 a
Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), [RhCp*Cl2]2
4 NaOAc PhCl 60 21 (7 mol %), CsOAc (0.3 mmol), DCE (1 mL), 100 °C, 24 h. bIsolated
5 NaOAc MeOH 60 20 yield.
6 NaOAc DMF 60 NDc
7 NaOAc dioxane 60 7
8 KOAc DCE 60 41 methyl (1b), methoxy (1c), tert-butyl (1d), phenyl (1e),
9 CsOAc DCE 60 51 fluoro (1f), or chloro unit (1g) on the para-position of the
10 Cu(OAc)2 DCE 60 trace phenyl ring coupled smoothly with 2a to afford their respective
11 AgOAc DCE 60 trace products 3b−3g in moderate to good yields. It is also
12 HOAc DCE 60 17 noteworthy that the electronic nature of the phenyl moiety
13d CsOAc DCE 60 58 imposed some effect on this reaction as substrates bearing
14e CsOAc DCE 60 55 electron-donating groups generally afforded higher yields than
15d CsOAc DCE 80 62 those bearing an electron-withdrawing (EW) group (3b−3d vs
16d CsOAc DCE 100 71 3f−3g). In particular, 1h containing a strong EW trifluor-
17d CsOAc DCE 120 68 omethyl group on the phenyl ring was recalcitrant, and its
18d,f CsOAc DCE 100 ND corresponding product 3h was not obtained. For 1 bearing a
a
Reaction conditions: 1a (0.3 mmol), 2a (0.33 mmol), [RhCp*Cl2]2 meta-methyl group, the reaction took place regioselectively on
(7 mol %), additive (0.3 mmol), solvent (1 mL), air, 24 h. bIsolated the less hindered ortho-site to give 3i. Interestingly, the C−H
yields. cND: not detected. d0.45 mmol of 2a. e0.6 mmol of 2a. alkylation occurred exclusively at the more hindered site for
f
Without [RhCp*Cl2]2. the meta-fluoro substituted substrate to give 3j. Meanwhile,
reactions involving an ortho-methyl or ortho-methoxy-sub-
and its structure was confirmed by single crystal X-ray stituted phenyl moiety (1k, 1l, and 1m) afforded their
diffraction analysis (see the SI). Encouraged by this interesting corresponding products 3k, 3l, and 3m in relatively lower
preliminary result, we carried out a systematic optimization to yields. In addition, it was observed that 3-(naphthalen-2-yl)-3-
develop this transformation into a general protocol for efficient oxopropanenitrile could also take part in this reaction to afford
synthesis of functionalized benzofulvenes. Different solvents compound 3n. Subsequently, the coupling reaction was
such as DCE, toluene, PhCl, MeOH, DMF, and dioxane were extended to include benzoylmethylsulfones (1o, 1p, and 1q),
tested (entries 2−7), and DCE was found to be the optimal in which the reactions proceeded smoothly under standard
(entry 2). Next, KOAc, CsOAc, Cu(OAc)2, AgOAc, and reaction conditions to form compounds 3o−3q in good yields
HOAc were screened as the additive (entries 8−12), and the (72−74%). Furthermore, this reaction was found to be
yield of 3a improved to 51% with CsOAc (entry 9). compatible with ethyl benzoylacetate to give 3r in moderate
Furthermore, increasing the ratio of 1a to 2a from 1:1.1 to yield.
1:1.5 improved the yield of 3a to 58% (entry 13). The reaction Next, the applicability of various propargyl alcohols 2 was
run under different temperatures such as 80, 100, or 120 °C explored by using 1a as a model substrate, and the results are
47 DOI: 10.1021/acs.orglett.9b03858
Org. Lett. 2020, 22, 46−51
Organic Letters Letter

shown in Scheme 3. First, substrates bearing a 4-methyl-, 4- Scheme 5. Intermolecular Kinetic Isotope Effect Study (I)
methoxyl-, 4-chloro-, 4-nitro-, or 3-methyl-substituted phenyl

Scheme 3. Substrate Scope for the Synthesis of 3 (II)a,b

Scheme 6. Intermolecular Kinetic Isotope Effect Study (II)

Fourth, a mixture of 1a and tert-butyl (2-methyl-4-phenyl-

but-3-yn-2-yl)carbonate (4) was subjected to the standard
reaction conditions, from which the expected benzofulvene
product was not obtained (Scheme 7). This result demon-
strates the importance of the hydroxy group in the reaction.

a
Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), [RhCp*Cl2]2 Scheme 7. Control Experiment
(7 mol %), CsOAc (0.3 mmol), DCE (1 mL), 100 °C, 24 h. bIsolated
yield.

ring as the R3 moiety and two methyl units as the R4 and R5

moieties reacted with 1a smoothly to give products 3s−3w in
moderate to good yields (40−73%). In addition, 2-methyl-4-
(thiophen-2-yl)but-3-yn-2-ol reacted with 1a to give the
corresponding product 3x in 70% yield. Further studies
showed that the reactions of 2 bearing a cyclopropyl or butyl
group as the R3 moiety exhibited better efficiency than their
phenyl-substituted counterparts to give 3y−3bb in 70−83%
yields. When the R5 unit was changed from the methyl to ethyl
group, the reaction also proceeded efficiently to form 3cc.
Moreover, 1-(phenylethynyl)cyclopentanol and 1-
(phenylethynyl)cyclo-hexanol could take part in this reaction
to give 3dd−3gg in moderate to good yields (68−82%). The
structure of 3aa was confirmed by X-ray diffraction analysis
(see the SI).
To gain insight into the mechanism, 1a was treated with
D2O under standard reaction conditions for 12 h. This led to a
significant deuterium incorporation at the ortho-position of the
phenyl ring of 1a (Scheme 4).
To shed light on the mechanism and rationalize the regio-
and stereoselectivity observed above, extensive DFT studies
were carried out based on previous studies.13 Calculations to
first rationalize the regioselectivity of the reaction (see Scheme
8) for the migratory insertion step from Rhcpx1 and
equilibrium conformer Rhcpx1′ was carried out. The desired
regioisomer formed through TS0 from Rhcpx1 is lower in
energy than through TS0′, ΔΔG‡ = 1.8 kcal/mol (see Scheme
Scheme 8. Calculated Pathways for the 5-/6-Membered
Ring Cyclization Process (Values Are Solution Free
Energies in kcal/mol Relative to Rhcpx1)

Scheme 4. Study on the Reversibility of C−H Activation

Second, an intermolecular kinetic isotopic effect was

measured based on competition reactions between 1a with
2a and 1a-d5 with 2a. From this study, a kH/kD value of 4.0 was
determined (Scheme 5).
Third, parallel reactions of 1a with 2a and 1a-d5 with 2a
were carried out, from which a KIE value of 2.0 was obtained
(Scheme 6). These results (Schemes 5 and 6) suggest that C−
H bond cleavage might be the rate-determining step.
48 DOI: 10.1021/acs.orglett.9b03858
Org. Lett. 2020, 22, 46−51
Organic Letters
8). This preference could be attributed to the intramolecular
hydrogen bonding in Rhcpx1 and TS0. This selectivity
dominated by intramolecular hydrogen bonding is contrary
to the reported regioselectivity explained by electrostatic
interaction using NPA charge analysis. Our current calculations
suggest that the previously calculated pathway A for 6-
membered ring cyclization through transition state TS1 has a
free energy barrier of 20.6 kcal/mol relative to Rhcpx2 but
liberates highly unstable 3a′ and Cs[Cp*Rh(I)OAc] complex
(Scheme 8). The other route, pathway B, is facilitated by
CsOAc, and this first formed a very stable complex Rhcpx5,
−4.4 kcal/mol more exergonic than Rhcpx2. Studies have
proposed before that the cesium ion plays an important
activating role in reactions.14,15
The 5-membered ring closure in Rhcpx5 forms Rhcpx6
through an energetically feasible pathway via TS2 (ΔG‡ = 24.5
kcal/mol relative to Rhcpx5), and it would be converted to a
more stable Rhcpx7A through a proton transfer and ligand
exchange process, subsequently converted to a highly
thermodynamically stable product benzofulvene 3a via β-
hydroxo elimination through TS4A. The DFT calculations
show that pathway B forms a highly stable 3a (ΔG = −31.1
kcal/mol), and the reverse pathway will not be feasible
suggesting thermodynamic control over pathway B. In the
absence of CsOAc, however, the 5-membered ring closure is
kinetically less favorable through TS3 (ΔG‡ = 25.1 kcal/mol
relative to Rhcpx2) highlighting the importance of the acetate
salt in mediating this process. Further calculations on the
acetate salt additives and selectivity explaining preference for
E-isomer are available in the Supporting Information.
To illustrate the synthetic viability of the products obtained
above, several transformations were conducted. First, 3a was
treated with anhydrous AlCl3, affording (E)-2-(3-phenyl-2-
(prop-1-en-2-yl)-1H-inden-1-ylidene)acetonitrile (5) in 89%
yield.16 Next, 3a was treated with zinc dust and ethyl 2-
bromoacetate in THF providing a mixture of ethyl (Z)-3-
amino-4-((E)-2-(2-hydroxypropan-2-yl)-3-phenyl-1H-inden-1-
ylidene)but-2-enoate (6) and 1,1-dimethyl-9-phenylindeno
[2,1-c]pyran-3(1H)-one (7) in yields of 15% and 60%,
respectively (Scheme 9). The structure of 7 was confirmed
by single crystal X-ray diffraction analysis (see the SI).
Scheme 9. Structural Elaboration of 3a
Finally, to explore whether this new method is suitable for
large scale synthesis, 5 mmol of 1a was reacted with 2a
affording 3a in a yield of 61% (Scheme 10).
In summary, we have developed a novel synthetic method-
ology for the facile synthesis of functionalized benzofulvenes
via Rh(III)-catalyzed cascade reactions of benzoyl acetonitrile/
Scheme 10. Large Scale Synthesis of 3a
49
Letter
methylsulfone/acetate with propargyl alcohols via C(sp2)−H
bond functionalization followed by an intramolecular carbo-
cyclization and gained mechanistic insights into this selective
reaction via computational and experimental studies. Com-
pared with literature methods, the protocol developed herein
has major advantages such as ready availability of starting
materials, industrially relevant products, high atom-economy,
and excellent regio- and stereoselectivity. Studies on the search
for more applications of propargyl alcohols as coupling
partners in C(sp2)−H bond functionalizations are currently
under way in our laboratories.
■ ASSOCIATED CONTENT
* Supporting Information
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03858.
Experimental procedures, characterization data, NMR
spectra of all products, X-ray crystal structures, and data
of 3a, 3aa, and 7 (PDF)
Computational discussion and method (PDF)
Accession Codes
CCDC 1956460, 1956462, and 1956471 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail: richmond_lee@sutd.edu.sg.
*E-mail: xuesen.fan@htu.cn.
ORCID
Xinying Zhang: 0000-0002-3416-4623
Richmond Lee: 0000-0003-1264-4914
Xuesen Fan: 0000-0002-2040-6919
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (NSFC) (21572047), Plan for Scientific Innovation
Talents of Henan Province (184200510012), Program for
Innovative Research Team in Science and Technology in
Universities of Henan Province (20IRTSTHN005), Key
Project of Science and Technology of Henan Province
(192102310412), 111 Project (D17007), and Singapore
University of Technology and Design (T1MOE1706 and
SUTD-MIT IDC grant IDG31800104) for financial support.
Computational resources from the National Supercomputing
Centre (Singapore) are gratefully acknowledged.
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