Synthesis of 2 h-chromenes via hydrazine-catalyzed ring-closing carbonyl-olefin metathesis

Article abstract of DOI:10.1021/acscatal.9b03656

The catalytic ring-closing carbonyl-olefin metathesis (RCCOM) of O-Allyl salicylaldehydes to form 2H-chromenes is described. The method utilizes a [2.2.1]-bicyclic hydrazine catalyst and operates via a [3 + 2]/retro-[3 + 2] metathesis manifold. The nature of the allyl substitution pattern was found to be crucial, with sterically demanding groups such as adamantylidene or diethylidene offering optimal outcomes. A survey of substrate scope is shown along with a discussion of mechanism supported by DFT calculations. Steric pressure arising from syn-pentane minimization of the diethylidene moiety is proposed to facilitate cycloreversion.

Full text of DOI:10.1021/acscatal.9b03656

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Letter
Synthesis of 2H-Chromenes via Hydrazine-
Catalyzed Ring-Closing Carbonyl-Olefin Metathesis
Yunfei Zhang, Janis Jermaks, Samantha N. MacMillan, and Tristan H. Lambert
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03656 • Publication Date (Web): 10 Sep 2019
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ACS Catalysis
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Synthesis of 2H-Chromenes via Hydrazine-Catalyzed Ring-Closing Carbonyl-Olefin
Metathesis
Yunfei Zhang, Janis Jermaks, Samantha N. MacMillan, and Tristan H. Lambert*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853
RECEIVED DATE (automatically inserted by publisher); Tristan.Lambert@Cornell.edu
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with all substrates and COM modalities. In fact, during the
course of this work, we have found that the attempted use of
ABSTRACT: The catalytic ring-closing carbonyl-olefin
acids to achieve the RCCOM of O-allyl salicylaldehydes 5 was
metathesis (RCCOM) of O-allyl salicylaldehydes to form
unproductive and resulted primarily in deallylation reactions
2H-chromenes is described. The method utilizes a [2.2.1]-
bicyclic hydrazine catalyst and operates via a [3+2]/retro-
[3+2] metathesis manifold. The nature of the allyl
substitution pattern was found to be crucial, with sterically
demanding groups such as adamantylidene or diethylidene
offering optimal outcomes. A survey of substrate scope is
shown along with a discussion of mechanism supported by
DFT calculations. Steric pressure arising from syn-pentane
minimization of the diethylidene moiety is proposed to
facilitate cycloreversion.
(vide infra). Thus, alternative strategies are required if this and
other COM reactions are to be fully realized.
A.
OMe
F
Cl
O
O
Ph
O
O
O
N
H
Cl
Me
1
2
3
hildgardtene
BW683C
(antiviral)
(antidiabetic)
(pesticide)
OMe
B.
Keywords: Carbonyl-olefin metathesis • hydrazines • chromenes •
O
cycloaddition • cycloreversion
R
R
R1
OH
O
The 2H-chromene architecture and its derivatives are
common motifs in biologically relevant molecules,1,2 including
for example the antiviral compound BW683C (1),3 the pesticide
hildgardtene (2),4 and the antidiabetic compound 3 (Figure
1A).5 Accordingly, many synthetic strategies have been devised
to access 2H-chromenes 7,6 and the development of novel
strategies remains a valuable undertaking. One conceptually
attractive approach to 2H-chromene synthesis is via ring-
closing double-bond metathesis,7,8 particularly because such
strategies can capitalize on the widespread availability of
salicylaldehydes 49 and the trivial nature of their conversion to
allyl ethers 5 (Figure 1B).10 Most notably, Grubbs has reported
the use of olefin metathesis to convert dienes to the
corresponding 2H-chromenes.7 However, a drawback to this
approach is that it requires an additional step to convert the
aldehyde moiety of 5 into an alkene, which thus incurs the costs
of additional time, waste, and potential substrate
incompatibility. A more desirable strategy would be to convert
aldehydes 5 directly into chromenes 7 via catalytic ring-closing
carbonyl-olefin metathesis (RCCOM). Unfortunately,
carbonyl-olefin metathesis (COM) technologies remain
relatively underdeveloped, and only in recent years have the
first catalytic strategies been reported.11-13 Indeed, the first
catalytic RCCOM reactions were described by Schindler in
2016 using Lewis acid catalysis,14 while others have
subsequently shown that a variety of Lewis15 and Brønsted
acids16 can catalyze such reactions with certain substrates.
While these works have greatly expanded the scope of
carbonyl-olefin metathesis, acid catalysis is not compatible
4
7
NH
2H-chromenes
salicylaldehydes
(readily available)
N
H
8
O
R3
R1
O
alkylation
R2 R3
R2
R3
R
6
Br
carbonyl-olefin
metathesis
O
R1 R2
5
C.
R
H
R
H
O
O
N
N
HX
H2O
H2O
hydrazine-
catalyzed
carbonyl-olefin
metathesis
R
R
+
N
R
R
+
N
X–
X–
N
N
H
H
R
R
HX
N
N
Figure 1. (A) Bioactive 2H-chromenes. (B) Conversion of
salicylaldehydes to chromenes. (B) Hydrazine-catalyzed carbonyl-
olefin metathesis.
In 2012 we described a novel approach to carbonyl-olefin
metathesis that employed hydrazine catalysts and proceeded via
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Page 2 of 7
a thermally-allowed [3+2] cycloaddition / cycloreversion
supporting information for details). Changing the ring size
offered no improvements in this regard (9f, 9g, entries 6 and 7).
More productively, the use of an adamantylidene ethyl ether
(9h) resulted in reasonable yield (30%) in relation to the amount
of starting material conversion (40%, entry 8). The most
effective group proved to be 3,3-diethylallyl (9i, entry 9), which
resulted in the highest yield of 10, with minimal amounts of
starting material lost to deallylation. Extension to isopropyl
groups was not beneficial however (9j, entry 10). The
efficiency of the diethylallyl substrate is striking, particularly in
comparison to the dimethyl (entry 4) and cyclohexylidene
(entry 5) substrates. These results suggest that the ethyl groups
play an important role in facilitating this catalytic process, and
we propose a hypothesis for their impact in the mechanistic
discussion section.
Next, we conducted an optimization study of the RCCOM of
salicylaldehyde ether 9i in order to maximize the yield of
chromene (10) and to minimize unwanted side products (Table
2). First, a screen of solvents revealed that the reaction occurred
in a variety of media (entries 1-4), but EtOH proved to be
optimal in terms of conversion and formation of the desired
product 10. At a lower temperature of 120 ºC, a lower
conversion and product yield were obtained in the same
reaction time (entry 5). Because it has been shown that certain
substrates can undergo carbonyl-olefin metathesis reactions
under Brønsted acid catalysis,16 we examined this reaction in
the presence of TFA alone (entry 6). While we observed 100%
conversion of starting material, no desired chromene 10 was
obtained, demonstrating that the hydrazine plays a crucial role
in the optimized process. We also examined whether Lewis
acid conditions14,15 would promote this reaction (entry 7).
Again, no desired product was formed, and only deallylated
salicylaldehyde was obtained.
1
2
3
4
5
6
7
8
sequence (Figure 1C).11 Using this strategy, we developed a
catalytic ring-opening carbonyl-olefin metathesis (ROCOM) of
cyclopropenes. That chemistry was greatly facilitated by the
release of ring strain during both the cycloaddition and
cycloreversion events,17 and it was thus unclear whether the
strategy could be extended to realize the RCCOM of O-
allylsalicylaldehydes 5 to form 2H-chromenes 7.
Table 1. Allyl group screen.a
9
10 mol%
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
O
R1
NH
•2TFA
O
N
R2
H
8
+
R1 R2
11
O
O
CH3CN, 140 ºC
12 h
9
10
entry
1
substrate
2 consumption (%) 3 yield (%) salicylaldehyde yield (%)
H
H
13
29
32
51
86
90
80
40
65
27
0
0
3
5
9a
Ph
H
2
9b
9c
Ph
Ph
Me
Me
3
0
15
5
4
13
31
10
30
30
48
3
9d
9e
5
5
6
10
7
9f
7
9g
9h
8
2
Table 2. Optimization studies.a
Et
9
2
9i
9j
Et
10 mol%
catalyst
O
Et
O
i-Pr
i-Pr
+
10
3
Et
9i
Et
Et
solvent
sealed vial, 12 h
O
O
11i
10
a Conditions: substrate 9 (0.2 mmol) and catalyst 8•(TFA)2 (10 mol %)
in 1.0 mL of solvent in a 5 mL sealed tube were heated to 140 C for
12 h. Conversions and yields were determined by 1H NMR using
CH2Br2 as an internal standard.
entry
catalyst
solvent
temp. (ºC)
conv. (%)
3 yield (%)
1
8• (TFA)2
8• (TFA)2
8• (TFA)2
8• (TFA)2
8• (TFA)2
TFA
CH3CN
DCE
140
140
140
140
120
140
rt
65
49
48
2
20
3
MeOH
EtOH
EtOH
EtOH
DCE
100
100
85
40
To investigate this possibility, we began by examining the
reaction of a series of O-allyl salicylaldehydes 9, in which the
substitution of the alkylidene fragment was varied (Table 1).
For this screen, we used 10 mol% [2.2.1]-bicyclic hydrazine
8•(TFA)2 as the catalyst,18 with acetonitrile solvent heated to
140 ºC in a sealed vial for 12 h. The main products observed in
these reactions included the desired 2H-chromene 10 and
salicylaldehyde (not shown) resulting from deallylation. The
ketone products 11 were not isolated. In varying the allyl
fragment, we found that an allyl group itself (9a) led to little
conversion and no desired product (entry 1). Cinnamyl (9b) and
3,3-diphenylallyl (9c) groups were similarly unproductive
(entries 2 and 3). On the other hand, the use of a prenyl group
(9d) led to appreciable consumption of starting material, albeit
with only 13% yield of the desired chromene 10 (entry 4). A
cyclohexylidene ethyl ether (9e) resulted in a notable
improvement in consumption of starting material and in the
generation of the desired product (entry 5), although the yield
of 10 was limited by competing intramolecular ene reaction (see
4
78 (73)b
5
47
0
6 c
100
100
7
FeCl3
0
a Conditions: substrate 9i (0.2 mmol) and 10 mol % catalyst in 1.0 mL
of solvent in a 5 mL sealed tube were heated to the temperature
indicated for 12 h. Conversions and yields were determined by 1H
b
c
NMR using CH2Br2 as an internal standard. Isolated yield; 20 mol
% TFA was used.
Before discussing our scope studies, we note that substrate
synthesis is straightforward and scalable (Scheme 1). Thus, 3-
pentanone (11i) could be converted to ester 13 in 85% yield by
Horner-Wadsworth-Emmons reaction. Reduction of 13 with
DIBAL followed by treatment with PBr3 then furnished the
allyl bromide 14 in 82% yield. Notably, this three-step
procedure requires no chromatography and provides access to
14 on preparative scale (24.7 g). Finally, reaction of
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salicylaldehyde (15) with 14 in the presence of K2CO3 yielded
the metathesis substrate 9i in 92% yield.
heterocycles including indole, benzofuran, and benzothiophene
were innocuous in the reaction (42-44, entries 5-7). Similarly,
an unprotected alcohol, carboxylic acid, and amide were
unscathed in the reaction and offered no inhibition to the
metathesis (45-47, entries 8-10). Two functionalities were
found to not be unscathed: an unprotected aniline (48, entry 11)
and an alkyl bromide (49, entry 12). Although the metathesis
product 10 was still produced, the yield was diminished
somewhat in both cases, and the additives were recovered in
low yield. These last two examples notwithstanding, the
functional group compatibility of this method appears to be
reasonably broad.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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32
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Substrate scope studies for hydrazine-catalyzed RCCOM of
Scheme 1. Synthesis of metathesis substrate 9i.
salicylaldehyde allylic ethers.a
Using the conditions defined in entry 4 of Table 2, we
explored the substrate scope of this process (Table 3). In
addition to the unsubstituted case 10 (entry 1), we found alkyl
(18, entry 2), halogen (19-21, entries 3-5), and methoxy
substitution (22, entry 6) at the 7-position of the chromene
system to be well-tolerated. Substitution at the 6-position also
proved possible, as alkyl (23 and 24, entries 7 and 8), halogen
(25 and 26, entries 9 and 10), and trifluoromethoxy (27, entry
11) substituted products were accessed in good to excellent
yields. Electron-withdrawing groups in the form of a nitro or
carbomethoxy substituent could also be accommodated (28 and
29, entries 12 and 13), albeit in lower yields. Meanwhile,
substitution of the 8-position with either a methyl or an allyl
group proved possible (30 and 31, entries 14 and 15),
demonstrating that encumbrance of the ether oxygen is not
detrimental to reactivity and that the presence of a distal olefin
is compatible with the reaction. Substitution next to both the
ether and carbonyl functionalities was also tolerated (entry 16).
Two RCCOM reactions on the same substrate was possible
using increased catalyst loading (33, entry 17), and a fused
aromatic ring system in the form of 3H-benzo[f]chromene (34)
could also be generated with this method (entry 18).
Although the standard conditions were less accommodating
to substitution on the pyran ring, we found that slight
modifications enabled productive reactions to occur. Thus,
while 2-methyl chromene 35 was generated in only 18% yield
with the standard procedure, switching to i-PrOH as solvent and
the use of 20 mol% catalyst increased the yield to 75% (entry
19). Similarly, a low yield of less than 20% of 36 was improved
to 45% yield with these same modifications (entry 20). On the
other hand, the reaction of a ketone instead of an aldehyde-
containing substrate remained problematic (37, entry 21). We
suspect that condensation of the hydrazine and/or cycloaddition
is quite challenging with this substrate, and thus the design of
catalysts with less steric demand may be necessary for this class
of substrates.
Although the elevated reaction temperature for this method
might raise questions about functional group compatibility, we
note that the conditions are relatively mild. To illustrate this
a Conditions: substrate (0.1 mmol) and catalyst 8•(TFA)2 (10 mol %)
in 0.5 mL of ethanol were heated to 140 C in a 5 mL sealed tube for
12 h. Yields were determined on purified products. b 20 mol% catalyst
used. c Isopropanol was used as solvent.
19
point, we conducted a functional group compatibility screen
as shown in Table 4, using the ROCOM reaction of 9i as our
standard. We found that electron-rich alkyne and alkene
functionality were well-tolerated (38 and 39, entries 1 and 2),
as was a ketone (40, entry 3). Notably, a basic pyridine did not
undergo decomposition and did not inhibit the reaction to any
appreciable extent (41, entry 4). Potentially sensitive
A description of the catalytic cycle for this reaction is shown
in Figure 2. Hydrazine catalyst 8•(TFA)2 condenses with
aldehyde 9i to generate hydrazonium intermediate 50.
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Intramolecular 1,3-dipolar cycloaddition between the
1
hydrazonium moiety and the olefin then furnishes the
pentacyclic intermediate 51a. After proton migration between
nitrogen atoms to generate 51b, cycloreversion reveals the
chromene adduct 10 and hydrazonium 52. Finally, hydrolysis
of 52 unveils 3-pentanone (11i) and returns the hydrazine 8 to
the catalytic cycle.
2
3
4
5
6
7
8
9
Table 4. Functional group compatibility screen for hydrazine-
catalyzed ROCOM.a,b
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
Figure 2. Mechanistic rationale for hydrazine 8-catalyzed RCCOM of
O-allyl salicylaldehyde 9i.
To better understand the reaction pathway and to help
rationalize the optimal performance of the diethyl allyl moiety,
we conducted DFT calculations for each step of the presumed
reaction pathway for substrate 9i (Figure 3). Condensation of
catalyst 8•(TFA)2 with 9i to form hydrazonium 50 is mildly
exergonic. The energy barrier for cycloaddition (cf. 53) is
modest at 19.8 kcal/mol, and indeed we have found this reaction
proceeds, albeit slowly, at room temperature. A favorable
proton migration event between the two nitrogens following the
cycloaddition leads to 51b, which is overall 20.2 kcal/mol more
stable than the cycloaddition precursor 50. As anticipated, the
cycloreversion event (cf. 54) is the rate-determining step, with
an energy barrier for the diethyl substrate 54i of 38.8 kcal/mol.
Interestingly, while the transition state energies for the allyl
(54a) and prenyl (54d) substrates were found to be higher (42.2
and 40.4 kcal/mol respectively), the cyclohexylidene (54e) and
adamantylidene (54h) substrates had significantly lower
a Yields of 10 were determined by 1H NMR. b Values in parentheses
refer to amount of recovered additive as determined by 1H NMR.
Figure 3. Calculated energies for hydrazine 8-catalyzed RCCOM of salicylaldehyde ether 9i. Energies were calculated at the M06-2X/6-
311+G(d,p)/PCM(ethanol) level of theory. All energies are given in kcal/mol.
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Supporting Information Available: Experimental procedures
and product characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
barriers (33.1 and 35.0 kcal/mol) than the diethyl substrate. The
reason why the cyclohexylidene substrate is less effective is due
to the competition of an intramolecular ene reaction (see
supporting information for details). Both the adamantylidene
and diethyl substrates offer high yields under the optimal
conditions, which we believe is a combination of accessible
cycloreversion activation energies and steric protection from
deallylation of the starting material. Interestingly, the
cycloreversion to generate 2H-chromene (10) is calculated to
be slightly endergonic (+2.9 kcal/mol), as is the subsequent
hydrolysis of hydrazonium 52 to form 3-pentanone (11i) and
catalyst 8 (+1.9 kcal/mol). Overall, each catalyst turnover only
becomes irreversible once the next cycloaddition has taken
place, and thus the resting state of the catalyst is the cycloadduct
51b.
1
2
3
4
5
6
7
8
References
1. Pratap, R.; Ram, V. J. Natural and Synthetic Chromenes, Fused Chromenes,
and Versatility of Dihydrobenzo[h]chromenes in Organic Synthesis. Chem.
Rev. 2014, 114, 10476-10526.
2. For example: (a) Rochfort, S.; Metzger, R.; Hobbs, L.; Capon, R. New
Chromenols From a Southern Australian Tunicate, Aplidium solidum. Aust.
J. Chem. 1996, 49, 1217-1219. (b) Covington, A. D. Modern Tanning
Chemistry. Chem. Soc. Rev. 1997, 26, 111-126. (c) Jankun, J.; Selman, S.
H.; Swiercz, R.; Skrzypczak-Jankun, E. Why Drinking Green Tea Could
Prevent Cancer. Nature 1997, 387, 561-561. (d) Rensburg, H. v.; Heerden,
P. S. v.; Bezuidenhoudt, B. C. B.; Ferreira, D. Enantioselective Synthesis of
the Four Catechin Diastereomer Derivatives. Tetrahedron Lett. 1997, 38,
3089-3092.
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
In further support of this analysis, we were able to prepare
the cycloadduct 51b in 90% yield by combining an equimolar
mixture of salicylaldehyde ether 9i and hydrazine 8•(TFA)2 in
EtOH at 80 ºC (Scheme 2). The molecular structure of this
cycloadduct obtained by X-ray crystallography confirms the
3. Bauer, D. J.; Selway, J. W. T.; Batchelor, J. F.; Tisdale, M.; Caldwell, I. C.;
Young, D. A. B. 4’,6-Dichloroflavan (BW683C), a new anti-rhinovirus
compound. Nature 1981, 292, 369-370.
4. (a) Monache, F. D.; Labbiento, L.; Marta, M.; Lwande, W. 4-Substituted
Flavans from Tephrosia Hildebrandtii. Phytochemistry 1986, 25, 1711-
1713. (b) Machocho, A. K.; Lwande, W.; Jondiko, J. I.; Moreka, L. V. C.;
Hassanali, A. Three New Flavanoids from the Root of Tephrosia Emoroides
and Their Antifeedant Activity Against the Larvae of the Spotted Stalk
Borer Chilo Partellus Swinhoe. Int. J. Pharmacogn. 1995, 33, 222-227.
5. Yasunaga, T.; Kimura, T.; Naito, R.; Kontani, T.; Wanibuchi, F.;
Yamashita, H.; Nomura, T.; Tsukamoto, S.-i.; Yamaguchi, T.; Mase, T.
Synthesis and Pharmacological Characterization of Novel 6-Fluorochroman
Derivatives as Potential 5-HT1A Receptor Antagonists. J. Med. Chem. 1998,
41, 2765-2778.
6. For a review on 2H-chromene synthesis, see: Majumdar, N.; Paul, N. D.;
Mandal, S.; Bruin, B. d.; Wulff, W. D. Catalytic Synthesis of 2H-
Chromenes. ACS Catal. 2015, 5, 2329-2366.
7. Chang, S.; Grubbs, R. H. A Highly Efficient and Practical Synthesis of
Chromene Derivatives Using Ring-Closing Olefin Metathesis. J. Org.
Chem. 1998, 63, 864-866.
8. Bera, K.; Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. Iron-Catalyzed Synthesis
of Functionalized 2H-Chromenes via Intramolecular Alkyne-Carbonyl
Metathesis. J. Org. Chem. 2011, 76, 3539-3544.
9. Salicylaldehydes can be prepared by the ortho formylation of phenols.
Olah, G. A.; Ohannesian, L.; Arvanaghi, M. Formylating Agents. Chem.
Rev. 1987, 87, 671-686.
10. Rohlmann, R.; Daniliuc, C.-G.; Mancheño, O. G. Highly Enantioselective
Synthesis of Chiral 7-Ring O- and N-Heterocycles by a One-Pot Nitro-
Michael–Cyclization Tandem Reaction. Chem. Commun. 2013, 49, 11665-
11667.
11. Griffith, A. K.; Vanos, C. M.; Lambert, T. H. Organocatalytic Carbonyl-
Olefin Metathesis. J. Am. Chem. Soc. 2012, 134, 18581-18584.
12. For reviews of carbonyl-olefin metathesis, see: (a) Lambert, T. H.
20
expected stereochemistry. When this material was heated to
140 ºC in EtOH for 2 h, 2H-chromene (10) was produced in
75% isolated yield, thus confirming that the cycloadduct 51b is
a viable intermediate for this catalytic procedure. We note that
the gem-diethyl group of cycloadduct 51 adopts a classic syn-
pentane minimized conformation (blue arrow). We speculate
that in doing so, this structural feature exerts a steric pressure
(red arrows) that facilitates cycloreversion. Such steric pressure
could rationalize the even greater impact of the adamantylidene
group as well.
O
NH
O
Et
• 2TFA
F3C
O–
N
O
H
N
8
H
H
H
Et
EtOH, 80 ºC
O
N
51b
Et
90% yield
9i
Et
syn
pentane
EtOH, 140 ºC
2 h
O
75% yield
10
51b
X-ray
Scheme 2. Synthesis, X-ray structure, and cycloreversion of
cycloadduct 51b. Atoms are shown with an ellipsoid probability of
50%, and all hydrogen atoms except for the one bound to N1 have been
omitted for clarity.
Development of
a Hydrazine-Catalyzed Carbonyl-Olefin Metathesis
Reaction. Synlett, 2019, DOI: 10.1055/s-0039-1689924. (b) Ludwig, J. R.;
Schindler, C. S. Lewis Acid Catalyzed Carbonyl–Olefin Metathesis. Synlett
2017, 28, 1501-1509. (c) Ravindar, L.; Lekkala, R.; Rakesh, K. P.; Asiri,
A. M.; Marwani, H. M.; Qin, H.-L. Carbonyl–Olefin Metathesis: A Key
Review. Org. Chem. Front. 2018, 5, 1381-1391. (d) Groso, E. J.; Schindler,
C. S. Recent Advances in the Application of Ring-Closing Metathesis for
the Synthesis of Unsaturated Nitrogen Heterocycles. Synthesis 2019, 51,
1100-1114.
The current method offers an efficient new approach to
synthesize
2H-chromenes
from
readily
available
salicylaldehyde ethers. More broadly, this work advances the
use of hydrazine catalysis for carbonyl-olefin metathesis to the
context of ring-closing reactions. The optimal behavior of
sterically demanding groups for these reactions provides
important guidance for the pursuit of other RCCOM methods.
13. Becker, M. R.; Watson, R. B.; Schindler, C. S. Beyond Olefins: New
Metathesis Directions for Synthesis. Chem. Soc. Rev. 2018, 47, 7867-7881.
14. Ludwig, J. R.; Zimmerman, P. M.; Gianino, J. B.; Schindler, C. S. Iron(III)-
Catalysed Carbonyl–Olefin Metathesis. Nature 2016, 533, 374-379.
15. (a) Ma, L.; Li, W.; Xi, H.; Bai, X.; Ma, E.; Yan, X.; Li, Z. FeCl3-Catalyzed
Ring-Closing Carbonyl–Olefin Metathesis. Angew. Chem. Int. Ed. 2016, 55,
10410-10413. (b) McAtee, C. C.; Riehl, P. S.; Schindler, C. S. Polycyclic
Aromatic Hydrocarbons via Iron(III)-Catalyzed Carbonyl–Olefin
Metathesis. J. Am. Chem. Soc. 2017, 139, 2960-2963. (c) Groso, E. J.;
Acknowledgement: Financial support for this work was provided
by NIH R35 GM127135.
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Golonka, A. N.; Harding, R. A.; Alexander, B. W.; Sodano, T. M.;
Schindler, C. S. 3-Aryl-2,5-Dihydropyrroles via Catalytic Carbonyl-Olefin
Metathesis. ACS Catal. 2018, 8, 2006-2011. (d) Ni, S.; Franzén, J.
Carbocation Catalysed Ring Closing Aldehyde–Olefin Metathesis. Chem.
Commun. 2018, 54, 12982-12985. (e) Tran, U. P. N.; Oss, G.; Breugst, M.;
Detmar, E.; Pace, D. P.; Liyanto, K.; Nguyen, T. V. Carbonyl–Olefin
Metathesis Catalyzed by Molecular Iodine. ACS Catal. 2018, 912-919. (f)
Tran, U. P. N.; Oss, G.; Pace, D. P.; Ho, J.; Nguyen, T. V. Tropylium-
Promoted Carbonyl–Olefin Metathesis Reactions. Chem. Sci. 2018, 9,
5145-5151. (g) Albright, H.; Riehl, P. S.; McAtee, C. C.; Reid, J. P.;
Ludwig, J. R.; Karp, L. A.; Zimmerman, P. M.; Sigman, M. S.; Schindler,
C. S. Catalytic Carbonyl-Olefin Metathesis of Aliphatic Ketones: Iron(III)
Homo-Dimers as Lewis Acidic Superelectrophiles. J. Am. Chem. Soc. 2019,
141, 1690-1700.
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42
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44
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46
47
48
49
50
51
52
53
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55
56
57
58
59
60
16. Catti, L.; Tiefenbacher, K. Brønsted Acid-Catalyzed Carbonyl-Olefin
Metathesis inside a Self-Assembled Supramolecular Host. Angew. Chem.
Int. Ed. 2018, 57, 14589-14592.
17. Hong, X.; Liang, Y.; Griffith, A. K.; Lambert, T. H.; Houk, K. N.
Distortion-Accelerated Cycloadditions and Strain-Release-Promoted
Cycloreversions in the Organocatalytic Carbonyl-Olefin Metathesis. Chem.
Sci. 2014, 5, 471-475.
18. Lambert, T. H.; Griffith, A. K. 2,3-Diazabicyclo[2.2.1]heptane.
Encyclopedia
of
Reagents
for
Organic
Synthesis
2014,
doi:10.1002/047084289X.rn01779.
19 . Collins, K. D.; Glorius, F. Intermolecular Reaction Screening as a Tool for
Reaction Evaluation. Acc. Chem. Res. 2015, 48, 619-627.
20. Crystallographic data for compound 51b are available free of charge from
the Cambridge Crystallographic Data Centre under CCDC 1919817.
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