The Cyclohexa-2,5-dienyl Group as a Placeholder for Hydrogen: Organocatalytic Michael Addition of an Acetaldehyde Surrogate

Article abstract of DOI:10.1002/chem.202003764

An aldehyde with a cyclohexa-2,5-dienyl group in the α-position is introduced as a storable surrogate of highly reactive acetaldehyde. The cyclohexa-2,5-dienyl unit is compatible with an enantioselective Michael addition to nitroalkenes promoted by a Haya

Full text of DOI:10.1002/chem.202003764

Accepted Article
Accepted Article
Title: The Cyclohexa-2,5-dienyl Group as a Placeholder for Hydrogen:
Organocatalytic Michael Addition of an Acetaldehyde Surrogate
Authors: Weiqiang Chen, Huaquan Fang, Kaixue Xie, and Martin
Oestreich
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To be cited as: Chem. Eur. J. 10.1002/chem.202003764
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10.1002/chem.202003764
Chemistry - A European Journal
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The Cyclohexa-2,5-dienyl Group as a Placeholder for Hydrogen:
Organocatalytic Michael Addition of an Acetaldehyde Surrogate
Weiqiang Chen+, Huaquan Fang+, Kaixue Xie, and Martin Oestreich*
Abstract: An aldehyde with a cyclohexa-2,5-dienyl group in the α
position is introduced as a storable surrogate of highly reactive
acetaldehyde. The cyclohexa-2,5-dienyl unit is compatible with an
enantioselective Michael addition to nitroalkenes promoted by a
Hayashi–Jørgensen catalyst and can be removed by a boron Lewis
acid-mediated C–C bond cleavage. The robust two-step sequence
does not require a large excess of the aldehyde component that is
typically needed when directly using acetaldehyde.
such as transfer hydrocyanation[7a] and hydromethallylation[7b]
have been accomplished. We anticipated that a cyclohexa-2,5-
dienyl unit α to a carbonyl group could be degraded the same
way (5→6), hoping that it would also be compatible with an
organocatalytic Michael reaction (4→5; Scheme 1, bottom).
Being part of the carbon skeleton, the cyclohexa-2,5-dienyl
substituent nevertheless fulfils the role of a placeholder for a
hydrogen atom.
Acetaldehyde, paraldehyde, and new surrogate in organocatalysis
The direct use of readily available acetaldehyde (1) as a C2
building block is synthetically attractive.[1] However, a low boiling
point (bp. 20 °C) together with severe toxicity complicates
handling of this highly reactive chemical. It is therefore
particularly impressive that 1 can be engaged as the nucleophilic
reactant in various enantioselective transformations catalyzed by
proline or congeners such as Hayashi–Jørgensen catalysts.[2–4]
For example, List[4a] as well as Hayashi[4b] independently
reported Michael additions with nitroalkenes to yield γ-
nitroaldehydes with excellent enantiocontrol. Poelarends and co-
workers had similar success with a proline-based tautomerase
as catalyst.[4c,e] To avoid the delicate manipulation of volatile 1,
Pericàs and co-workers turned toward employing liquid
paraldehyde (2; bp. 124 °C) that hydrolyzes in acidic medium.
O
O
O
O
H
H
O
1
3
work of List, Hayashi,
and Poelarends
2
this work
work of Pericàs
Strategy: Michael addition followed by C–C bond cleavage
O2N
O
O
H
chiral amine
H
R
as catalyst
NO2
+
R
4
3
5
H
H
BX3
With
a sulfonic acid resin, high enantioselectivities were
O2N
R
release of
boron Lewis acid
O
O2N
BX3
H
obtained in the aforementioned reaction in the presence of a
polystyrene-supported Hayashi–Jørgensen catalyst.[5] Despite
these important advances, alternative methods that bypass the
use of 1 and 2 are still in demand.
O
H
– PhH
R
H
H
6
We introduce here the new user-friendly acetaldehyde
surrogate 3 (Scheme 1, top). The design of 3 emerges from
observations made during our investigations of boron Lewis
acid-catalyzed ionic transfer processes with cyclohexadiene-
based reagents.[6] To be precise, we had shown that nucleofugal
carbon groups attached to one of the saturated positions of the
cyclohexadiene can be abstracted by certain boron Lewis acids
with cleavage of a C–C bond.[7] The outcome is an ion pair
composed of a boron ate complex and a Brønsted acidic
Wheland intermediate that can either react with itself or with an
added reaction partner. By this, alkene hydrofunctionalizations
Scheme 1. Acetaldehyde in organocatalysis and application of a new
surrogate.
Acetaldehyde surrogate 3 was prepared on gram scale by
metalation of cyclohexa-1,4-diene followed by electrophilic
substitution with 2-bromo-1,1-dimethoxyethane and subsequent
acidic hydrolysis of the acetal (see the Supporting Information
for the detailed procedure). Despite being an aldehyde, 3 can be
stored in the freezer for months with no sign of decompostion.
Treatment of 3 with BF3·OEt2 resulted in the desired degradation
into acetaldehyde (1) and benzene (not shown), thereby
verifying the validity of the strategy outlined above. The Michael
addition did not require much optimization. Starting from List’s
and Hayashi’s reaction conditions with (S)-7[8] as catalyst,[4a,b] we
found that, depending on the scale of the reaction, either no
solvent or just a few drops of CH2Cl2 are needed and that the
reaction can be run open to air.[9] Moreover, the key difference to
the known protocols was that 2.0 equiv of 3 were sufficient to
reach high conversion within 24 h at room temperature. With
freshly distilled acetaldehyde, a 5.0-fold excess[4a] (stock solution
of 1) or a 10-fold excess[4b] (neat 1) were required. The model
[*]
[+]
W. Chen,[+] Dr. H. Fang,[+] K. Xie, Prof. Dr. M. Oestreich
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
These authors contributed equally in this work
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202003764
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reaction afforded the product in 80% yield with 99% ee and
moderate diastereoselection[10] (4a→5a; Scheme 2). Purification
by flash chromatography on silica gel improved the
diastereomeric ratio from 82:18 to 96:4, and this enantio- and
diastereoenriched sample allowed for growing single crystals
suitable for X-ray diffraction;[11] the relative configuration is as
shown (see the Supporting Information). The model reaction on
a 5.0 mmol scale afforded 82% yield with 99% ee and d.r. =
87:13.
This Michael addition turned out to be broadly applicable
with superb functional-group tolerance (Scheme 2). The majority
of the reactions were run at high concentration in CH2Cl2.
Nitroalkenes 4b–e with a methoxy or methyl group at the aryl
substituent in the β position and mono- and trihalogenated 4f–j
gave consistently high yields and enantiomeric excesses. A β-
naphthyl and a fur-3-yl group as in 4k and 4l were also
compatible. Electron-withdrawing substituents in aryl-substituted
nitroalkenes 4m–q were tolerated, including carboxy, cyano, and
nitro groups as well as a boronate pinacol ester. Likewise, alkyl-
O2N
O
O
(S)-7
substituted
nitroalkenes
4r–t
showed
excellent
Ph
Ph
(10 mol%)
H
R
H
enantioselectivities and good yields. These Michael adducts
were chemically stable for extended periods of time when kept in
the freezer.
NO2
N
+
R
H
OSiMe3
(S)-7
CH2Cl2
RT for 24 h
4a–t
3 (2.0 equiv)
5a–t
(X-ray for 5a and 5q)
The deprotection step, that is the removal of the cyclohexa-
2,5-dienyl unit, by acid-mediated C–C bond cleavage did work
as planned (5a→6a; Table 1). However, treatment of the model
compound with B(C6F5)3, the boron Lewis acid typically used in
our transfer chemistry,[6,7] required 18 h for completion (entry 1).
Conversely, the reaction was significantly faster with BF3·OEt2,
and full conversion was reached within 2 h (entry 2). Unlike the
boron Lewis acid-catalyzed transfer reactions, stoichiometric
amounts of either B(C6F5)3 or BF3·OEt2 were necessary. We
explain this by the presence of the nitro group. Hence,
substoichiometric quantities of BF3·OEt2 led to prolonged
reaction times (entry 3) while overstoichiometric amounts
furnished the desired aldehyde within minutes (entry 4). A
Brønsted acid such as TfOH as a promoter was also possible
but caused partial decomposition (entry 5).
Aryl-substituted nitroalkenes
5a (X = H): 80%, d.r. = 94:6 (82:18), 99% ee
5b (X = 4-OMe): 91%, d.r. = 85:15 (90:10), 99% ee
5c (X = 3-OMe): 85%, d.r. = 87:13 (92:8), 96% ee
5d (X = 4-Me): 93%, d.r. = 95:5 (90:10), 96% ee
5e (X = 2-Me): 86%,[a] d.r. = 87:13 (89:11), 95% ee
5f (X = 4-Br): 87%, d.r. = 92:8 (86:14), 93% ee
5g (X = 4-Cl): 99%, d.r. = 94:6 (85:15), 93% ee
5h (X = 3-Cl): 82%, d.r. = 86:14 (87:13), 97% ee
5i (X = 4-F): 95%, d.r. = 92:8 (96:4), 97% ee
O2N
O
X
O2N
O2N
O2N
F
O
O
O
O
F
F
5j: 84%[b]
d.r. = 79:21 (95:5)
99% ee
5k: 94%
d.r. = 88:12 (91:9)
95% ee
5l: 65%
d.r. = 76:24 (86:14)
86% ee
Table 1. Selected examples of the optimization of the acid-promoted C–C
bond cleavage.[a]
O2N
5m (X = CF3): 96%, d.r. = 83:17 (79:21), 97% ee
5n (X = CO2Me): 98%,[c] d.r. = 82:18 (85:15), 96% ee
5o (X = CN): 92%, d.r. = 81:19 (87:13), 98% ee
5p (X = NO2): 85%, d.r. = 81:19 (78:22), 97% ee
5q (X = Bpin): 78%,[b] d.r. = 88:12 (86:14), 92% ee
O
X
Alkyl-substituted nitroalkenes
Entry
Acid [equiv]
Time [h]
Conversion[b]
O2N
O2N
Me
O2N
1
2
3
4
5
B(C6F5)3 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (0.20)
BF3·OEt2 (1.5)
TfOH (1.0)
18
2
full
Me
O
O
O
full
48
¼
1
full
5r: 85%
d.r. = 91:9 (80:20)
93% ee[d]
5s: 88%[c]
d.r. = 79:21 (78:22)
97% ee[d]
5t: 76%[c]
d.r. = 69:31
97% ee[d]
full
full[c]
Scheme 2. Michael addition of acetaldehyde surrogate to nitroalkenes
catalyzed by a Hayashi–Jørgensen catalyst. All reactions were performed on a
0.10 to 0.20 mmol scale with the isolated yield determined after flash
chromatography on silica gel. Diastereomeric ratios (d.r.) estimated by 1H
NMR analysis after purification (those of the crude product in parentheses),
and enantiomeric excesses (ee) determined by HPLC analysis on chiral
stationary phases. [a] Reaction time of 62 h. [b] 4.0 equiv of 3 and reaction
time of 48 h. [c] Reaction time of 39 h. [d] Aldehyde reduced to the
corresponding alcohol prior to HPLC analysis. pin = pinacolato.
[a] A solution of the Michael adduct (0.04 mmol) in CD2Cl2 (0.5 mL) was
treated with the indicated acid at room temperature until full conversion was
reached. [b] Estimated by 1H NMR analysis. [c] Impurities observed. Tf =
trifluoromethanesulfonyl.
The standard protocol with 1.5 equiv of BF3·OEt2 was then
applied to the whole range of Michael adducts 5 (Scheme 2).
The BF3·OEt2-mediated C–C bond cleavage was successful for
the majority of substrates (5→6; Scheme 3). Electron-rich aryl
groups in 5 were an exception, and anisyl-substituted 5b and 5c
as well as furyl derivative 5l decomposed independent of the
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acid employed. The aliphatic substrates 5r–t participated with
similar success. No loss of the stereochemical information was
seen in any of these reactions. The NMR spectroscopic
characterization of aldehydes 6 was done immediately after their
preparation, including the measurement of the optical rotation.
However, the carbonyl group was converted into the
corresponding dithiolane by acetalization or alcohol by
borohydride reduction for the HPLC analysis. The absolute
configuration was assigned by comparison with literature-known
optical rotations and retention times (see the Supporting
Information for details).
equiv of the surrogate instead of n-fold excess of highly reactive
acetaldehyde) and avoidance of toxic acetaldehyde as a whole.
Acknowledgements
This research was supported by the China Scholarship Council
through predoctoral fellowships to W.C. (2016−2020) and K.X.
(2019–2023), the Alexander von Humboldt Foundation through a
postdoctoral fellowship to H.F. (2018–2020), and the Deutsche
Forschungsgemeinschaft (Oe 249/18-1). M.O. is indebted to the
Einstein Foundation Berlin for an endowed professorship. We
thank Dr. Elisabeth Irran for the X-ray analyses, Dr. Guoqiang
Wang for fruitful discussions (both TU Berlin), and Luisa
Giarrana (FU Berlin) for her experimental contributions.
O2N
O
O2N
BF3·OEt2 (1.5 equiv)
O
R
H
CH2Cl2
RT for ¼ h
– PhH
R
H
5
6
Keywords: acetaldehyde • C–C bond formation • Michael
Derived from aryl-substituted nitroalkenes
addition • organocatalysis • synthetic methods
O2N
6a (X = H): 86%, 99% ee[a]
6d (X = 4-Me): 92%, 91% ee[b]
F
O2N
6e (X = 2-Me): 96%, 95% ee[c]
O
[1]
[2]
For relevant reviews, see: a) S. M. Kim, Y. S. Kim, D. W. Kim, R. Rios,
J. W. Yang, Chem. Eur. J. 2016, 22, 2214–2234; b) M. Kumar, A.
Kumar, M. A. Rizvi, B. A. Shah, RSC Adv. 2015, 5, 55926–55937.
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Córdova, W. Notz, C. F. Barbas III, J. Org. Chem. 2002, 67, 301–303;
b) Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem. Int. Ed.
2008, 47, 2082–2084; Angew. Chem. 2008, 120, 2112–2114; c) Y.
Hayashi, S. Samanta, T. Itoh, H. Ishikawa, Org. Lett. 2008, 10, 5581–
5583; d) T. Urushima, Y. Yasui, H. Ishikawa, Y. Hayashi, Org. Lett.
2010, 12, 2966–2969; e) S. Hu, L. Zhang, J. Li, S. Luo, J.-P. Cheng,
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Eur. J. 2013, 19, 7143–7150.
6f (X = 4-Br): 99%, 95% ee[a]
F
O
6g (X = 4-Cl): 94%, 94% ee[a]
X
F
6h (X = 3-Cl): 97%, 96% ee[c]
6i (X = 4-F): 99%, 96% ee[c]
6j: 99%
99% ee[c]
O2N
6m (X = CF3): 98%, 97% ee[a]
6n (X = CO2Me): 91%, 97% ee[c]
6o (X = CN): 93%, 99% ee[c]
6p (X = NO2): 93%, 97% ee[c]
6q (X = Bpin): 78%, 92% ee[c]
O2N
O
O
X
6k: 93%
99% ee[a]
Derived from alkyl-substituted nitroalkenes
O2N
O2N
Me
O2N
[3]
Selected examples of the use of acetaldehyde in Mannich reactions: a)
J. W. Yang, C. Chandler, M. Stadler, D. Kampen, B. List, Nature 2008,
452, 453–455; b) Y. Hayashi, T. Okano, T. Itoh, T. Urushima, H.
Ishikawa, T. Uchimaru, Angew. Chem. Int. Ed. 2008, 47, 9053–9058;
Angew. Chem. 2008, 120, 9193–9198; c) C. Chandler, P. Galzerano, A.
Michrowska, B. List, Angew. Chem. Int. Ed. 2009, 48, 1978–1980;
Angew. Chem. 2009, 121, 2012–2014; d) T. Kano, R. Shakamoto, Y.
Yamaguchi, K.-i. Itoh, K. Maruoka, Chem. Commun. 2013, 49, 1118–
1120.
Me
O
O
O
6r: 99%
6s: 94%
6t: 82%
95% ee[a]
97% ee[b]
96% ee[b]
Scheme 3. BF3·OEt2-mediated C–C bond cleavage for the release of the
acetaldehyde-derived Michael adducts. All reactions were performed on a
0.050 to 0.15 mmol scale with the isolated yield determined after work-up and
the removal of solvents. [a] Compound converted into the corresponding
dithiolane prior the measurement of the enantiomeric excess by HPLC
[4]
Selected examples of the use of acetaldehyde in Michael reactions: a)
P. García-García, A. Ladépêche, R. Halder, B. List, Angew. Chem. Int.
Ed. 2008, 47, 4719–4721; Angew. Chem. 2008, 120, 4800–4802; b) Y.
Hayashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem. Int. Ed. 2008,
47, 4722–4724; Angew. Chem. 2008, 120, 4797–4799; c) E. Zandvoort,
E. M. Geertsema, B.-J. Baas, W. J. Quax, G. J. Poelarends, Angew.
Chem. Int. Ed. 2012, 51, 1240–1243; Angew. Chem. 2012, 124, 1266–
1269; d) Y. Qiao, J. He, B. Ni, A. D. Headley, Adv. Synth. Catal. 2012,
354, 2849–2853; e) E. M. Geertsema, Y. Miao, P. G. Tepper, P. De
Haan, E. Zandvoort, G. J. Poelarends, Chem. Eur. J. 2013, 19, 14407–
14410; f) X.-L. Meng, T. Liu, Z.-W. Sun, J.-C. Wang, F.-Z. Peng, Z.-H.
Shao, Org. Lett. 2014, 16, 3044–3047.
analysis on
corresponding alcohol prior the measurement of the enantiomeric excess by
HPLC analysis on chiral stationary phase. [c] Enantiomeric excesses
a chiral stationary phase. [b] Compound reduced to the
a
determined by HPLC analysis on a chiral stationary phase.
We presented here an alternative preparation of Michael
adducts formally derived from nitroalkenes and acetaldehyde.
The approach is based on an acetaldehyde surrogate with a
cyclohexa-2,5-dienyl substituent α to the carbonyl group as a
placeholder for a hydrogen atom. The two-step sequence
consists of a highly enantioselective Michael addition of that
surrogate promoted by a Hayashi–Jørgensen catalyst and a mild
removal of the ‘protecting group’ by C–C bond cleavage with
BF3∙OEt2. Aside from broad functional-group tolerance, the main
advantages are a favorable stoichiometry of the reactants (2.0
[5]
[6]
For using paraldehyde as an alternative source of acetaldehyde, see: C.
R. E. X. Fan, S. Sayalero, M. A. Pericàs, Chem. Eur. J. 2013, 19,
10814–10817.
For the reviews of metal-free ionic transfer processes based on
cyclohexadiene platforms, see: a) J. C. L. Walker, M. Oestreich, Synlett
2019, 30, 2216–2232; b) S. Keess, M. Oestreich, Chem. Sci. 2017, 8,
4688–4695; c) M. Oestreich, Angew. Chem. Int. Ed. 2016, 55, 494–
499; Angew. Chem. 2016, 128, 504–509.
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[7]
a) P. Orrechia, W. Yuan, M. Oestreich, Angew. Chem. Int. Ed. 2019, 58,
3579–3583; Angew. Chem. 2019, 131, 3617–3621; b) J. C. L. Walker,
M. Oestreich, Angew. Chem. Int. Ed. 2019, 58, 15386–15389; Angew.
Chem. 2019, 131, 15530–15534; for transfer hydrohalogenation also
involving C–C bond cleavage in the surrogate, see: c) W. Chen, J. C. L.
Walker, M. Oestreich, J. Am. Chem. Soc. 2019, 141, 1135–1140; d) W.
Chen, M. Oestreich, Org. Lett. 2019, 21, 4531–4534.
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Angew. Chem. 2012, 124, 13321–13325; b) D. Seebach, X. Sun, M.-O.
Ebert, W. B. Schweizer, N. Purkayastha, A. K. Beck, J. Duschmalé, H.
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Chim. Acta 2013, 96, 799–852.
[8]
[9]
For a review of diarylprolinol silyl ethers, see: B. S. Donslund, T. K.
Johansen, P. H. Poulsen, K. S. Halskov, K. A. Jørgensen, Angew.
Chem. Int. Ed. 2015, 54, 13860–13874; Angew. Chem. 2015, 127,
14066–14081.
[11] CCDC 2007922 (5a) and 2007923 (5q) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
We note here that related surrogates with a quaternary carbon atom in
the C1 position of the cyclohexa-2,5-dienyl unit did not react.
Apparently, aldehydes with a neopentylic α carbon atom are sterically
too hindered. The preparation of these surrogates is outlined in the
Supporting Information.
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Suggestion for the Entry for the Table of Contents
COMMUNICATION
W. Chen+, H. Fang+, K. Xie, M. Oestreich*
Page No. – Page No.
The Cyclohexa-2,5-dienyl Group as a
Placeholder for Hydrogen: Organocatalytic
Michael Addition of an Acetaldehyde
Surrogate
Strength of a weak bond. A cyclohexa-2,5-dienyl group covalently bound to the α
carbon atom of acetaldehyde can be carried through an enantioselective Michael
reaction promoted by a Hayashi–Jørgensen catalyst. Its mild removal by Lewis
acid-mediated C–C bond cleavage liberates Michael adducts formally derived from
highly reactive acetaldehyde (see scheme). Unlike reactions involving the direct
use of acetaldehyde, no large excess of the surrogate is necessary.
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