Metathesis Reaction of Diazo Compounds and para-Quinone Methides for C-C Double Bond Formation: Synthesis of Tetrasubstituted Alkenes and Quinolinones

Article abstract of DOI:10.1021/acs.orglett.6b02365

The para-quinone methides (p-QMs) are activated by Lewis acid and then attacked by diazo compounds. The following rearrangement leads to nitrogen gas extrusion and C-C double bond formation to constitute a metathesis reaction process. Therefore, the diazo

Full text of DOI:10.1021/acs.orglett.6b02365

Letter
pubs.acs.org/OrgLett
Metathesis Reaction of Diazo Compounds and para-Quinone
Methides for C−C Double Bond Formation: Synthesis of
Tetrasubstituted Alkenes and Quinolinones
Bo Huang,† Yangyong Shen,† Zhenjun Mao,† Yu Liu,‡ and Sunliang Cui*,†
‡
†Institute of Drug Discovery and College of Pharmaceutical Sciences, and State Key Laboratory of Plant Physiology and
Biochemistry, College of Life Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
S
* Supporting Information
ABSTRACT: The para-quinone methides (p-QMs) are activated by Lewis acid and then
attacked by diazo compounds. The following rearrangement leads to nitrogen gas extrusion and
C−C double bond formation to constitute a metathesis reaction process. Therefore, the
diazoester is transformed into tetrasubstituted alkenes, whereas the diazo-oxindole delivers the
quinolinone products. Furthermore, the 13C-labeling experiments were also conducted to
elucidate a possible mechanism.
he reaction with new modes of a C−C double bond
(DCE). The reaction was initially carried out at −20 °C, and no
new products were observed (Table 1, entry 1). When 4 Å
powder molecular sieves were added as the additive, surprisingly,
gas extrusion was observed while a new product 3a was formed
and isolated with a moderate yield (entry 2). Standard
characterization including NMR and MS analysis was not able
to identify the structure. To our delight, a crystal of the
compound was obtained, and the X-ray analysis confirmed the
T
formation is highly important and a challenging task in
organic synthesis.1 The classical methods rely on Wittig reaction
and Tebbe olefination from phosphorus ylides and Tebbe’s
reagents.2 The McMurry reaction represents another method
toward double bond formation, with carbonyl compounds as
starting materials and Zn/TiCl4 as reductants.3 On the other
hand, the transition metal alkylidene-catalyzed metathesis
reaction constitutes a facile and efficient strategy for approaching
alkenes, demonstrating powerful utility in both academia and
industry.4 Recently, Lambert invented a remarkable organo-
catalytic carbonyl olefin metathesis reaction to obtain the C−C
double bond.5 Therefore, development of a metal alkylidene
catalyst-free metathesis reaction for the construction of the C−C
double bond is interesting and important.
a
Table 1. Optimization of the Reaction Conditions
The para-quinone methides (p-QMs), which are structurally
characterized by the assembly of carbonyl and olefinic moieties,
exhibit unique chemical reactivity as a precursor of phenols.6
Recently, p-QMs have been widely utilized as a Michael acceptor
in various conjugate addition reactions, especially the asymmetric
form.7
Diazo compounds are important and versatile building blocks
in organic synthesis. The well-known transition-metal-catalyzed
transformations of diazo compounds to carbenoids and their
diversified reactivities have been well-developed.8 Besides, diazo
compounds also serve as mild nucleophilic reagents to carbonyls
under acidic reaction conditions.9−12 Therefore, exploration of
diazo compounds with new reactivity, especially with new modes
of C−C bond formation, remains attractive and interesting.
In continuation of our efforts in diazo compound trans-
formation and heterocycle synthesis,13 herein, we report a
metathesis reaction of diazo compounds and p-QMs toward C−
C double bond formation for accessing tetrasubstituted alkenes
and quinolinones.
b
entry
Lewis acid
amount of 2a
solvent
yield (%)
c
1
TiCl4
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
2 equiv
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
DCE
DCM
trace
63
2
TiCl4
3
BF3−Et2O
SnCl4
Cu(OTf)2
TiCl4
trace
trace
trace
77
4
5
6
7
TiCl4
3 equiv
81
8
TiCl4
4 equiv
95
9
TiCl4
4 equiv
78
10
TiCl4
4 equiv
trace
68
d
11
e
TiCl4
4 equiv
12
TiCl4
4 equiv
42
a
Reaction conditions: 1a (0.2 mmol), Lewis acid (20 mol %), solvent
(1 mL), 4 Å powder molecular sieves (20 mg), run at −20 °C under
argon for 8 h. Isolated yields. Without molecular sieves. Run at −10
b
c
d
e
°C. Run at −78 °C.
We commenced our study by investigating p-QMs 1a and
Received: August 8, 2016
diazoester 2a with TiCl4 as the Lewis acid in dichloroethane
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
structure to be tetrasubstituted alkene.14 Moreover, we were
interested to find that the two phenyl rings were cleaved from
their original p-QMs and diazo skeleton, indicating an
unprecedented metathesis reaction in this process. Next, a
variety of Lewis acids were screened to optimize the reaction
conditions. It was found that BF3−Et2O, SnCl4, and Cu(OTf)2
were inferior (entries 3−5). The amount of diazoester 2a was
then increased and could improve the yield dramatically (entries
6 and 7). When the amount was increased to 4 equiv, the yield
could be ultimately improved to 95% (entry 8). A survey of the
solvents showed that DCM was effective but led to a lower yield,
while the use of THF resulted in trace product formation (entries
9 and 10). Additionally, either increasing the temperature to −10
°C or decreasing the temperature to −78 °C would diminish the
yield (entries 11 and 12).
QM 1h was subject to the reaction, the process could proceed
smoothly to furnish product 3k in good yield. Mechanistically,
when the aromatic ring substitutions of p-QMs and diazoester
were differential, this process was expected to furnish a mixture of
E/Z isomers. Indeed, a variety of p-QMs and diazoesters with
differential aromatic rings were subject to the reaction, and this
metathesis process furnished inseparable E/Z isomers of alkenes.
For example, the reaction of p-QM 1a (with a phenyl ring) and
diazoester 2e (with a 4-tolyl ring) afforded alkene 3l as a mixture,
and the single-crystal X-ray analysis disclosed the structure of E/
Z isomers.16 Therefore, the combinations of p-QMs and
diazoesters enable the formation of diverse tetrasubstituted
alkene formation (3m−3t). The functional groups, such as
cyano, nitro, and naphthanyl, were compatible in this process.
Interestingly, variation of diazoester to diazo-oxindole 2k to
react with 1a under standard reaction conditions delivered trace
alkene product. The next optimization found that when the
amount of TiCl4 was increased to 1 equiv and the molecular
sieves were removed, an unprecedented reaction would occur
between p-QMs and diazo-oxindole for accessing product 4a in
63% yield (eq 1). The structure was confirmed by X-ray analysis,
With the optimized reaction conditions in hand, we set out to
explore the generality of this process (Scheme 1). Various tert-
Scheme 1. Scope of the Metathesis Reaction toward
a
Tetrasubstituted Alkenes
and a chloro atom was found to be incorporated on the benzyl
group, which should originate from TiCl4.17 The next attempt of
AlCl3-promoted de-tert-butylation led to a rearrangement to
funrnish quinolinone product 5a.
Next, we were pleased to find that the two steps could be
merged as a one-pot metathesis reaction toward C−C double
bond formation for quinolinone synthesis (Scheme 2). Various
substituted p-QMs were subjected to this process to furnish the
quinolinones in moderate yields. Notably, the functional groups
were well-tolerated in this protocol, such as chloro and bromo,
Scheme 2. Scope of the Metathesis Reaction toward
a
Quinolinones
a
Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), TiCl4 (0.2 mmol),
DCE (2 mL), run at −20 °C under argon for 8 h; yields refer to
isolated products.
butyl-tethered p-QMs and diazoesters with the same aromatic
ring substitution were subject to the reaction and proceeded well
to furnish the tetrasubstituted alkenes. In these cases, the same
aromatic ring substitution excluded the formation of E/Z
isomers. Variation of the ester to 2-bromoethyl, 2-methylallyl,
and propargyl would lead to the corresponding functional
products, albeit in a slightly lower yield (3b−3d), and those
functional groups would offer the opportunity for further
derivation. A variety of substituted p-QMs and diazoesters with
substitution, such as methyl, methoxy, chloro, or bromo, were
also applicable in this metathesis process to produce the
tetrasubstituted alkenes (3e−3j) in moderate to excellent yields.
Furthermore, the single-crystal X-ray analysis of 3e confirmed
the structure again.15 In addition, when the methyl-tethered p-
a
Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), TiCl4 (0.2 mmol),
DCE (2 mL), run at −20 °C under argon for 4 h, then run at 70 °C in
benzene for 2 h; yields refer to isolated products.
B
DOI: 10.1021/acs.orglett.6b02365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thus offering an opportunity for further application. The
structure of compound 5c was confirmed by X-ray analysis.18
Moreover, the substituted diazo-oxindoles were also found to be
applicable in this process to furnish the desired phenol-
containing quinolinone products. Due to the wealth of
quinolinones in pharmaceuticals, this method represents a
distinct approach to these compounds.19,20
4) and regenerates TiCl4. Thus, this catalytic cycle constitutes a
metathesis process. With respect to the intermediate C that
originated from diazo-oxindoles, a direct chloride addition to the
benzyl cation gives F and the following protonation furnishes 4.
When 4 is treated with AlCl3, the de-tert-butylation and
dechlorination occur simultaneously to form cationic G, which
undergoes a sequential ring expansion to form quinolinones 5
with C−C double bond formation. Thus, the whole process
constitutes a metathesis reaction formation.
In conclusion, a metathesis reaction of p-QMs and diazo
compounds was developed toward C−C double bond formation.
The protocol could deliver tetrasubstituted alkenes and
quinolinones, while the process could also be scaled up.
Furthermore, 13C-labeling reactions were conducted to elucidate
a possible reaction mechanism.
To unravel the synthetic utility, we conducted a gram-scale
reaction. For example, a gram-scale reaction was conducted for
1a and 2a according to the procedure, and 1.58 g of 3a could be
furnished in 89.4% yield and could be applied to synthesis of the
desired molecules (see Supporting Information). Meanwhile, 0.7
g of 5c could be formed in 65% yield (see Supporting
Information).
To gain insight into the reaction mechanism, the 13C-labeling
reactions were conducted (Figure 1). The 13C-1a was
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02365.
Full experimental procedures, characterization data, and
NMR data (PDF)
Crystallographic data for 3a (CIF)
Crystallographic data for 3e (CIF)
Crystallographic data for 3l (CIF)
Crystallographic data for 4a (CIF)
Crystallographic data for 5c (CIF)
Figure 1. 13C-labeling reaction.
synthesized and subjected to reaction with 2a and 2k to generate
13C-3a and 13C-5a. For 13C-3a, the CNMR analysis shows that
the labeling carbon was cleaved with quinone and tethered with
two phenyl rings. With respect to 13C-4a, the labeling carbon is
found to be the methylene carbon tethering a chloro atom and
placed at the 4-position of the quinolinone moiety of 13C-5a.
Based on these experiments, a plausible reaction mechanism is
depicted in Figure 2. Initially, the p-QM 1 was activated by TiCl4
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: slcui@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from National Natural
Science Foundation of China (Nos. 21472163 and 31400224).
■
REFERENCES
■
(1) (a) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87. (b) Hoveyda,
A. H.; Zhugralin, A. R. Nature 2007, 450, 243.
(2) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(b) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978,
100, 3611.
(3) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708.
(4) (a) Villemin, D. Tetrahedron Lett. 1980, 21, 1715. (b) Chauvin, Y.
Angew. Chem. 2006, 118, 3824; Angew. Chem., Int. Ed. 2006, 45, 3740.
(c) Schrock, R. R. Angew. Chem. 2006, 118, 3832; Angew. Chem., Int. Ed.
2006, 45, 3748. (d) Grubbs, R. H. Angew. Chem. 2006, 118, 3845;
Angew. Chem., Int. Ed. 2006, 45, 3760. (e) Wilson, M. R.; Taylor, R. E.
Angew. Chem. 2013, 125, 4170; Angew. Chem., Int. Ed. 2013, 52, 2794.
(5) Griffith, A. K.; Vanos, C. M.; Lambert, T. H. J. Am. Chem. Soc. 2012,
134, 18581.
Figure 2. Proposed mechanism.
(6) (a) Turner, A. B. Q. Q. Rev., Chem. Soc. 1964, 18, 347. (b) Peter, M.
G. Angew. Chem. 1989, 101, 572; Angew. Chem., Int. Ed. 1989, 28, 555.
(c) Wagner, H.-U.; Gompper, R. Quinone Methides. In The Chemistry of
Quinonoid Compounds, Patai, S., Ed.; Wiley: New York, 1974; Vol 2, p
1145.
(7) (a) Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.; Zeng, C.; Du, J.-
Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. Angew. Chem. 2013,
125, 9399; Angew. Chem., Int. Ed. 2013, 52, 9229. (b) Caruana, L.; Kniep,
F.; Johansen, T. K.; Poulsen, P. H.; Jørgensen, K. A. J. Am. Chem. Soc.
2014, 136, 15929. (c) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.;
to form cationic intermediate A, which was trapped by diazo
compound 2 to give cyclopropanation intermediate B with
nitrogen extrusion. The quinone moiety is further activated by
TiCl4 for cyclopropane fragmentation to deliver cationic species
C. At this stage, a divergent transformation occurs. For those
diazoesters derived from C, the aromatic ring originates from
diazoesters undergoing migration to form D, and the following
hydrogen elimination transformed D to tetrasubstituted alkene
skeleton E. Finally, protonation of E furnishes the product (3 or
C
DOI: 10.1021/acs.orglett.6b02365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Liao, J. Angew. Chem. 2015, 127, 12302; Angew. Chem., Int. Ed. 2015, 54,
12134. (d) Dong, N.; Zhang, Z.-P.; Xue, X.-S.; Li, X.; Cheng, J.-P. Angew.
Chem. 2016, 128, 1482; Angew. Chem., Int. Ed. 2016, 55, 1460. (e) He,
F.-S.; Jin, J.-H.; Yang, Z.-T.; Yu, X.; Fossey, J. S.; Deng, W.-P. ACS Catal.
2016, 6, 652. (f) Zhao, K.; Zhi, Y.; Wang, A.; Enders, D. ACS Catal.
2016, 6, 657. (g) Jarava-Barrera, C.; Parra, A.; Lop
́
ez, A.; Cruz-Acosta,
F.; Collado-Sanz, D.; Cardenas, D. J.; Tortosa, M. ACS Catal. 2016, 6,
́
442. (h) Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 428.
(i) Deng, Y.-H.; Zhang, X.-Z.; Yu, K.-L.; Yan, X.; Du, J.-Y.; Huang, H.-
M.; Fan, C.-A. Chem. Commun. 2016, 52, 4183. (j) Zhang, X.-Z.; Deng,
Y.-H.; Yan, X.; Yu, K.-L.; Wang, X.-F.; Ma, X.-Y.; Fan, C.-A. J. Org. Chem.
2016, 81, 5655.
(8) (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (b) Davies,
H. M. L.; Hedley, S. J. Chem. Soc. Rev. 2007, 36, 1109. (c) Davies, H. M.
L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061.
(9) (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
(b) Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992, 33, 1131.
(c) Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J. Org. Chem. 1990,
55, 5297. (d) Evans, D. A.; Adams, D. J. J. Am. Chem. Soc. 2007, 129,
1048.
(10) (a) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L.;
Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532. (b) Li, W.; Tan, F.;
Hao, X.; Wang, G.; Tang, Y.; Liu, X.; Lin, L.; Feng, X. Angew. Chem.
2015, 127, 1628; Angew. Chem., Int. Ed. 2015, 54, 1608. (c) Li, W.; Liu,
X.; Hao, X.; Cai, Y.; Lin, L.; Feng, X. Angew. Chem. 2012, 124, 8772;
Angew. Chem., Int. Ed. 2012, 51, 8644.
(11) (a) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc.
2008, 130, 2434. (b) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am.
Chem. Soc. 2009, 131, 6614. (c) Hashimoto, T.; Naganawa, Y.; Maruoka,
K. J. Am. Chem. Soc. 2011, 133, 8834.
(12) Moebius, D. C.; Kingsbury, J. S. J. Am. Chem. Soc. 2009, 131, 878.
(13) (a) Cui, S.-L.; Wang, J.; Wang, Y.-G. J. Am. Chem. Soc. 2008, 130,
13526. (b) Cui, S.; Zhang, Y.; Wang, D.; Wu, Q. Chem. Sci. 2013, 4,
3912. (c) Zhang, Y.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 2494. (d) Cui,
S.; Zhang, Y.; Wu, Q. Chem. Sci. 2013, 4, 3421. (e) Zhang, Y.; Wu, Q.;
Cui, S. Chem. Sci. 2014, 5, 297. (f) Zheng, J.; Zhang, Y.; Cui, S. Org. Lett.
2014, 16, 3560. (g) Wu, Q.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 1350.
(h) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79, 6490. (i) Zhang,
Y.; Shen, M.; Cui, S.; Hou, T. Bioorg. Med. Chem. Lett. 2014, 24, 5470.
(j) Zheng, J.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 4572. (k) Zheng, J.;
Deng, Z.; Zhang, Y.; Cui, S. Adv. Synth. Catal. 2016, 358, 746. (l) Zheng,
J.; Qi, J.; Cui, S. Org. Lett. 2016, 18, 128. (m) Zheng, J.; Zhang, Y.; Wang,
D.; Cui, S. Org. Lett. 2016, 18, 1768. (n) Shen, Y.; Qi, J.; Mao, Z.; Cui, S.
2016, 18, 2722.
(14) 3a: CCDC 1449198.
(15) 3e: CCDC 1470628.
(16) 3l: CCDC 1470629.
(17) 4a: CCDC 1454863.
(18) 5c: CCDC 1491659.
(19) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: New York, 1996;
Vol. 5, p 167.
(20) Selected examples for synthesis quinolinones, see: (a) Li, X.; Li,
X.; Jiao, N. J. Am. Chem. Soc. 2015, 137, 9246. (b) Zhang, Z.; Liao, L.-L.;
Yan, S.-S.; Wang, L.; He, Y.-Q; Ye, J.-H.; Li, J.; Zhi, Y.-G.; Yu, D.-G.
Angew. Chem. 2016, 128, 7184; Angew. Chem., Int. Ed. 2016, 55, 7068.
D
DOI: 10.1021/acs.orglett.6b02365
Org. Lett. XXXX, XXX, XXX−XXX