[4 + 2]-Cycloaddition and 1,4-Addition of ortho-Quinone Methides by a Chiral Crotyl Silane

Article abstract of DOI:10.1021/acs.orglett.8b03395

Anhydrous FeCl₃ in the presence of 2,6-lutidine promotes the substrate-controlled enantioselective [4 + 2]-cycloaddition and crotylation reaction between an enantioenriched (S,E)-crotyl silane and in situ generated ortho-quinone methides (oQMs)

Full text of DOI:10.1021/acs.orglett.8b03395

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
[4 + 2]-Cycloaddition and 1,4-Addition of ortho-Quinone Methides
by a Chiral Crotyl Silane
Christopher R. Wong, Gerald Hummel, Yongqi Cai, Scott E. Schaus,* and James S. Panek*
Department of Chemistry, Metcalf Center for Science and Engineering, Boston University, 590 Commonwealth Avenue, Boston,
Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: Anhydrous FeCl3 in the presence of 2,6-lutidine promotes the substrate-controlled enantioselective [4 + 2]-
cycloaddition and crotylation reaction between an enantioenriched (S,E)-crotyl silane and in situ generated ortho-quinone
methides (oQMs). The reaction produces both the chiral chroman and crotylation products in a ratio reflective of the electronic
nature of the parent oQM with overall combined yields up to 96%. A ring-opening and elimination sequence was subsequently
developed to provide direct access to the crotylation products, containing two contiguous tertiary carbon stereocenters, in good
yields and enantioselectivities.
ortho-Quinone Methides (oQMs) are transient, reactive
intermediates that have demonstrated wide usage in organic
synthesis and pharmaceuticals.1 In light of their elusive nature,
significant efforts have been made toward selective reactions of
oQMs formed in situ, generating a 1,3-cyclohexadiene core
substituted with a carbonyl and an exocyclic methylene group
that can be represented by two canonical forms: a zwitterionic
or biradical species.2 This highly polarized structure renders
oQMs highly susceptible to reaction with nucleophiles in 1,4-
addition reactions as well as dienophiles in inverse electron-
demand [4 + 2] cycloaddition reactions, providing two unique
pathways toward rearomatization.3 Since the first demonstra-
tion of an asymmetric reaction of an oQM by Pettus, notable
advances have been made toward utilizing oQM intermediates
in asymmetric synthesis.4
Herein, we report an enantioselective FeCl3-promoted [4 +
2]-cycloaddition and 1,4-addition reaction between a chiral
crotyl silane and in situ generated oQMs to give the
corresponding stereochemically well-defined benzopyran and
1,4-addition products with useful levels of enantioselectivity. In
the process of our initial studies, key observations were made
that led to the development of a cycloaddition and subsequent
ring-opening reaction sequence that selectively yielded the 1,4-
addition product with two contiguous tertiary carbon stereo-
centers, which remains an important and challenging bond
construction to access selectively.5 Formally, this reaction
sequence can be considered an asymmetric crotylation of an
oQM, and to our knowledge, is the first example of such a
transformation.6
methide and allyl-TMS (Scheme 1).6b In their proposed two-
step sequence, an initial cycloaddition reaction between the
Scheme 1. Sajiki FeCl3 Catalyzed Sequential Cycloaddition
and 1,4-Addition of o-Naphthoquinone by Allyl-TMS
generated ortho-naphthoquinone methide (oNQM) and allyl-
TMS is followed by the formation of a para-naphthoquinone
methide that undergoes nucleophilic attack by a second
equivalent of allyl-TMS. The dual reactivity exhibited by allyl-
TMS highlights the ability of allyl silane reagents to function as
both nucleophiles in 1,4-conjugate addition reactions7 and
dienophiles in inverse electron-demand hetero-Diels−Alder
reactions.8 We have had a longstanding interest in developing
and utilizing related chiral silane reagents in asymmetric
reactions with a variety of reaction partners.9 In that context,
we intended to expand the use of these chiral silane reagents in
asymmetric reactions with oQMs.
The present work was inspired by studies reported by the
Schaus laboratory in which Fe(III) chloride salts were utilized
to promote the in situ formation and reaction of oQMs.10 The
reactivity of the oQM generated from o-hydroxybenzyl alcohol,
or diol, 1a, and allyl-TMS was initially examined (Table 1).
Recent work by the Sajiki laboratory has demonstrated the
potential for an allyl silane to utilize both of the
aforementioned oQM reaction pathways in their FeCl3-
catalyzed reaction between the related 1-naphthoquinone-2-
Received: October 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. [4 + 2] Cycloaddition and 1,4-Addition of o-
Quinone Methide by Allyl-TMS
Table 2. [4 + 2] Cycloaddition and 1,4-Addition of o-
Quinone Methide by (S)-Crotyl Silane 4
a
a
b
entry concn (M) time (h) yield 2 (%)
yield 3a (%) yield 3b (%)
FeCl3
lutidine
(equiv)
temp
yield 5a
b
yield 6a
c
1
2
3
4
5
6
0.5
0.25
0.1
0.1
0.05
0.05
18
18
18
1
18
1
0
0
36
49
72
72
42
61
33
35
20
21
22
17
1
1
0
entry
(equiv)
(°C)
(%)
(%)
1
2
3
0.8
0.8
0.8
0.4
0.6
0.4
0.6
0.4
0.4
0.4
0
0.3
0.2
0.6
rt
0
0
0
0
0
0
51
59
53
51
57
21
33
16
12
16
16
10
14
32
d
4
5
6
7
0
a
Reaction conditions: diol (0.25 mmol, 1 equiv), allyl-TMS (3 equiv),
FeCl3 (0.8 equiv with respect to diol), and 2,6-lutidine (0.4 equiv with
respect to diol). Diastereomeric ratio determined by 1H NMR.
a
b
Reaction conditions: diol (0.25 mmol, 1 equiv), (S)-crotyl silane (2
Isolated dr 1:1.
equiv), and 0.05 M with respect to 1a. Diastereromeric ratio
b
c
determined by 1H NMR. Single diastereomer. dr ranged from 3:1 to
d
22:1. Run at 0.1 M.
Anhydrous FeCl3 (0.8 equivalent) in the presence of 2,6-
lutidine (0.4 equivalent) at an initial concentration of 0.5 M at
room temperature afforded the 1,4-addition product in 42%
yield as the free phenol 3a and 22% yield as the silylated
phenol 3b, but no cycloaddition product 2 was observed
(Table 1, entry 1). Encouraged by this result, the reaction
concentration was lowered to 0.25 M, resulting in a small
increase in overall yield (Table 1, entry 2). Upon lowering the
reaction concentration further, mixtures of the cycloaddition
product 2 in addition to the allylation product 3a were
obtained (Table 1, entries 3−6). Decreasing the reaction time
to 1 h at 0.05 M ultimately gave an optimal overall yield of
93% combined for 2 and 3a (Table 1, entry 6).
We next sought to extend this [4 + 2]-cycloaddition and 1,4-
addition reaction of diol 1a to the chiral crotyl (S,E)-silane 4
(Table 2).11 Studies were initiated using the optimized
reaction conditions for allyl-TMS (Table 2, entry 1), which
gave a mixture of 51% of the cycloaddition product 5a and
16% of the 1,4-addition, or crotylation, product 6a. Lowering
the temperature to 0 °C (Table 2, entry 2) gave a markedly
cleaner reaction and an increase in overall yield to 71% of 5a,
in 59% yield as a single diastereomer, and 6a in 12% yield with
a 22:1 dr. Increasing the concentration (Table 2, entry 3) and
lowering the FeCl3 and 2,6-lutidine loading (Table 2, entries
5−7) all led to diminished overall yields. It was also noted that
the omission of 2,6-lutidine (Table 2, entry 4) resulted in a
lower yield with observed baseline byproducts, which indicated
the importance of the base as an acid scavenger to minimize
potential side reactions.
The optimized reaction conditions for (S,E)-silane 4 were
used to explore the substrate scope of the cycloaddition and
1,4-addition (Figure 1). A variety of diols bearing electron-rich
and electron-deficient substituents were evaluated and found
to be tolerated under the reaction conditions. Electron-
donating groups meta to the oQM methylene (1b, 1c) gave
only modest increases in overall yield for the corresponding
products relative to 1a. Interestingly though for substrate 1c, it
was noted that the relative ratio of cycloaddition 5c to
crotylation product 6c (10:1 ratio) increased almost 2-fold
Figure 1. FeCl3 and 2,6-lutidine mediated cycloaddition and
crotylation of diols by (S)-crotyl silane.a a Reaction conditions (unless
otherwise noted): 1 (0.25 mmol), 2 (2 equiv), FeCl3 (0.8 equiv), 2,6-
lutidine (0.4 equiv), and 0.05 M with respect to diol. Diastereromeric
1
ratios determined by H NMR. b FeCl3 (2.5 equiv) and 2,6-lutidine
(1.25 equiv). Detailed experimental conditions are provided in the
Supporting Information.
compared to the relative product ratios obtained for 1a and 1b
(5:1 ratio for each), which is consistent with a decrease in
electrophilicity and reactivity of a more electron-rich oQM
toward nucleophilic addition.12 Conversely, very strongly
electron-withdrawing substituents such as trifluoro (1g) and
B
DOI: 10.1021/acs.orglett.8b03395
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nitro (1h) favored the crotylation over the cycloaddition
product and gave comparable overall yields. Notably,
substitution with a halide onto the phenol of the diphenyl
diol substrates (1d−f) gave excellent overall yields with
product ratios slightly favoring the cycloaddition product.
Substitution on the R2 aryl ring (1k and 1l) was also well
tolerated, while substitution with a methyl group at that
position (1i, 1j) necessitated the stabilizing Br-substitution on
the phenol ring in order to achieve an appreciable overall yield.
Given the possibility that the crotylation products could
have arisen from an in situ ring opening of the pyran and silane
elimination (ring-opening reaction) of the generated cyclo-
addition products, 5a was isolated and resubjected to the
corresponding FeCl3/2,6-lutidine reaction conditions as well as
at room temperature (Scheme 2). However, conversion to 6a
was not observed in either case, which indicated the existence
of two potentially distinct reaction pathways to generate
products 5 and 6.
more forcing conditions were required to promote the
reaction. Upon changing the solvent to DCE and refluxing
overnight in the presence of BF3·OEt2, 6b was isolated in a
70% yield (Table 3, entry 7). A minor product from this
reaction was isolated and identified as the Z-isomer of 6b,
which was proposed to form from a potential E1-type
elimination of the silane moiety. When utilizing the strong
Lewis acid TiCl4, an optimal yield was achieved after only 3 h
at room temperature (Table 3, entry 8) as a mixture of 3:1 E/Z
isomers.
With the optimized conditions in hand, we then extended
this ring-opening reaction to utilize the crude product mixture
obtained from the FeCl3 promoted reaction between 1 and 4
(Figure 2). Gratifyingly, when subjecting the crude reaction
Scheme 2. Resubjection of 5a to Reaction Conditions
To further probe access to the crotylation products from the
corresponding cycloaddition products, conditions were
screened to promote a concomitant pyran ring opening and
silicon elimination of 5b (Table 3). Use of the fluoride ion
a
Table 3. Ring-Opening and Silicon Elimination of 5b
entry
promoter
promoter equiv
solvent
time (h) yield (%)
bc
,
1
2
TBAF
TBAF
NH4F
CsF
BF3·OEt2
BF3·OEt2
BF3·OEt2
TiCl4
8
20
20
20
6
30
5
3
THF
THF
THF
DMF
DCM
DCM
DCE
DCM
43
46
44
18
22
19
22
3
37
31
nr
nr
nr
nr
70
75
bd
,
e
3
f
4
Figure 2. TiCl4-promoted ring opening and silicon elimination of the
crude product mixture of 1 and 4.a a Reaction conditions (unless
otherwise noted): Ran general procedure for the FeCl3 and 2,6-
lutidine reaction to obtain crude product mixture of 5 and 6. To the
crude product mixture at 0 °C TiCl4 solution (1 M in DCM, 3 equiv)
was added, which was warmed to rt and stirred for 3 h. E/Z ratio and
dr determined by 1H NMR. Detailed experimental conditions are
provided in the Supporting Information.
5
6
7
g
h
i
8
a
Reaction conditions: 5b dissolved in given solvent, and reagent
b
added at 0 °C and stirred at rt unless otherwise stated. Reaction not
to completion. Isolated mix of 6b β,γ- and α,β-unsaturated isomers in
1:7 ratio. Ratio of 1:5 mix of 6b-β,γ/6b-α,β isomers. Reaction ran at
0.06 M. Reaction ran at 100 °C. Reaction ran at 70 °C. Ratio of
21:1 E/Z isomers and >30:1 dr. Ratio of 3:1 E/Z isomers and >30:1
c
d
e
f
g
h
i
product mixture of 1a and 4 to the TiCl4 mediated ring-
opening reaction conditions, 6a was obtained in 61% yield over
two steps. Good overall yields were obtained for substrates
containing electron-donating substituents (1b and 1c) and
demonstrated a unique approach to formally obtain 1,4-
addition products, despite the tendency for an electron-rich
parent oQM to discourage 1,4-addition. Substrates bearing
halide substituents in the diphenyl diol series (1d, 1e, 1f)
performed well under the ring-opening reaction conditions, in
accordance with the high overall yields observed in the initial
FeCl3-promoted reactions. Reactions of 1i and 1j also
dr.
source TBAF while stirring at room temperature gave
incomplete conversion, even with substoichiometric amounts
(Table 3, entries 1 and 2). Interestingly, a significant portion of
the product obtained was the isomerized α,β-unsaturated
isomer of 6b. Other fluoride sources such as NH4F and CsF
(Table 3, entries 3 and 4) as well the Lewis acid BF3·OEt2
(Table 3, entries 5 and 6) gave no reaction at room
temperature. The lack of reactivity observed suggested that
C
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demonstrated the importance of the initial FeCl3-promoted
reaction for the success of the subsequent ring-opening process
and provided a method to selectively access vicinal, methyl
tertiary stereocenters. Crotylation products containing two aryl
halide moieties (6k and 6l) were obtained in excellent yield
and were envisioned to enable future elaboration of the
crotylation products in a divergent fashion.
In conclusion, we have developed an enantioselective
cycloaddition and crotylation reaction of ortho-quinone
methides with a chiral (S,E)-crotyl silane reagent 4 in the
presence of the readily available and inexpensive promoter
FeCl3. The transformation provides access to both the chiral
pyran product 5 as well as the crotylation product 6 with two
contiguous tertiary carbon stereocenters. A TiCl4-mediated
ring opening of the pyran with concomitant elimination of
silicon, or formally a crotylation of the oQM, reaction sequence
was developed in the process to achieve the crotylation
product 6 in good to excellent yields. Studies focused on the
further elaboration and application of this methodology are
ongoing and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03395.
Experimental procedures and spectroscopy data for new
compounds (PDF)
(9) (a) Lee, J.; Panek, J. S. J. Org. Chem. 2015, 80, 2959. (b) Wu, J.;
Zhu, K.; Yuan, P.; Panek, J. S. Org. Lett. 2012, 14, 3624. (c) Wu, J.;
Panek, J. S. J. Org. Chem. 2011, 76, 9900. (d) Wu, J.; Becerril, J.; Lian,
Y.; Davies, H. M. L.; Porco, J. A., Jr.; Panek, J. S. Angew. Chem., Int.
Ed. 2011, 50, 5938. (e) Wu, J.; Chen, Y.; Panek, J. S. Org. Lett. 2010,
12, 2112. (f) Zhang, Y.; Panek, J. S. Org. Lett. 2009, 11, 3366.
(g) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J. S.
Org. Synth. 1998, 75, 78. (h) Masse, C. E.; Panek, J. S. Chem. Rev.
1995, 95, 1293. (i) Cai, B.; Evans, R. W.; Wu, J.; Panek, J. S. Org. Lett.
2016, 18, 4304.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: seschaus@bu.edu.
*E-mail: panek@bu.edu.
ORCID
Christopher R. Wong: 0000-0002-5132-3542
Scott E. Schaus: 0000-0002-5877-6587
Notes
(10) (a) Allen, E. E.; Zhu, C.; Panek, J. S.; Schaus, S. E. Org. Lett.
2017, 19, 1878. (b) Luan, Y.; Sun, H.; Schaus, S. E. Org. Lett. 2011,
13, 6480.
The authors declare no competing financial interest.
(11) (S,E)-Crotyl silane 4 was prepared in three steps from the
readily available 3-butyn-2-ol following the procedure detailed in ref
9g by the Panek laboratory.
(12) Weinert, E. E.; Dondi, R.; Colloredo-Metz, S.; Frankenfield, K.
N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc. 2006,
128, 11940.
ACKNOWLEDGMENTS
■
S.E.S. acknowledges the NIH for support (R01 GM078240).
The authors acknowledge preliminary studies performed by
Dr. Emily E. Allen (Boston University) and Dr. Yi Luan
(Boston University). The authors also thank Dr. Paul Ralifo
and Dr. Norman Lee at the Boston University Chemical
Instrumentation Center for helpful discussions and assistance
with NMR and HRMS.
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D
DOI: 10.1021/acs.orglett.8b03395
Org. Lett. XXXX, XXX, XXX−XXX