Addition of Chloroprene Grignards to Aromatic Aldehydes: Synthesis of Homoallenyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.1c00527

A general procedure for the one-pot synthesis of racemic homoallenyl alcohols from the corresponding aldehyde and chloroprene-derived Grignards is described. Employing bis[2-dimethylaminoethyl]ether (BDMAEE) as an additive at low temperatures shifts the selectivity of the chloroprene Grignard addition to aldehydes such that it is almost exclusive toward allene formation. In a set of follow-up experiments, simple and more elaborate methods for further derivatization have been demonstrated, allowing quick access to more complex structures.

Full text of DOI:10.1021/acs.orglett.1c00527

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Letter
Addition of Chloroprene Grignards to Aromatic Aldehydes:
Synthesis of Homoallenyl Alcohols
Arne G. A. Geissler and Bernhard Breit*
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ABSTRACT: A general procedure for the one-pot synthesis of
racemic homoallenyl alcohols from the corresponding aldehyde
and chloroprene-derived Grignards is described. Employing bis[2-
dimethylaminoethyl]ether (BDMAEE) as an additive at low
temperatures shifts the selectivity of the chloroprene Grignard
addition to aldehydes such that it is almost exclusive toward allene
formation. In a set of follow-up experiments, simple and more
elaborate methods for further derivatization have been demonstrated, allowing quick access to more complex structures.
ransition-metal-catalyzed allyic addition to allenes has
T
proven to be a high-performing alternative to the related
allylic substitution reaction.1 In particular, the homoallenyl
alcohol is a valuable building block in organic synthesis,2,3 as
demonstrated in our recent synthesis of rosuvastatin and
pitavastatin.4 The preparation of homoallenyl alcohols,
however, remains challenging, and practical protocols are
scarce.5
6
́
For laboratory purposes, the Crabbe reaction and its further
developed forms7 offer access to a broad range of terminal
allenes from the corresponding terminal alkyne. The same can
be achieved by chemoselective propargylic substitution with
aluminum hydride8 or via copper catalysis.9 Quantitative waste
and structural prerequisites make these approaches undesir-
able, yet sometimes necessary because of their flexibility.
Conversely, rearrangement reactions allow for the efficient
synthesis of homoallenyl esters10 and aldehydes.11 However,
due to the nature of the rearrangement reaction, the structural
flexibility of this approach is limited. More direct homo-
allenylation protocols of a carbonyl compound with suitable
precursors have been recently reported.12 These partially
enantioselective methods rely on toxic stannane or chromium
reagents, require a surplus of allenic precursor, or, in case of 2-
borylbuta-1,3-dienes, have to be synthesized in an expensive
multistep procedure.13
Regarding the described problems, we envisioned a simple
procedure for the γ-selective addition of a suitable 1,3-diene to
a carbonyl compound as the most applicable and straightfor-
ward approach for the synthesis of homoallenyl alcohols.
Among the typically polymerization labile 1,3-diene pronu-
cleophiles, we chose 2-chlorobuta-1,3-diene (chloroprene),
due to its industrial availability,14 which can be conveniently
converted into a Grignard reagent.15
alcohol 2a and 1,3-diene 3a (entry 1, Table 1).16
A
regioselectivity study of the chloroprene Grignard addition
reaction by Yamashita and Nunomoto revealed the influence of
different parameters, yet a reliable method for selective allene
formation in contrast to scarcely separable mixture of isomers
was not found.17
Received: February 13, 2021
Published: March 17, 2021
2-(1,3-Butadienyl)magnesium chloride (chloroprene
Grignard) was reported by Kondo and Matsumoto to react
with carbonyl compounds to form a mixture of homoallenyl
https://doi.org/10.1021/acs.orglett.1c00527
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2621−2625
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additive further enhances the already good results. Different
brominated substrates 1b−d gave good to very good yields and
selectivities. No significant side reaction was observed. For the
tolyl aldehydes 1e−g, the best selectivity was achieved for the
ortho substrate. The electron rich 1h, with the strongly
donating methoxy group in the para position, gave less good
regioselectivity. In comparison to the influence of the meta and
ortho substrate, this effect fades. In contrast, 1l−o performed in
the Grignard addition with almost perfect regioselectivity due
to their electron-withdrawing character. We were pleased to
find the cyano group in 1l remained intact under the reaction
conditions. Trifluoromethyl aryl substituted allenes 2n and 2o
were obtained in almost perfect selectivity with moderate yield.
Next to pyridine carbaldehydes, which gave good results, other
heterocycles were subjected to the reaction conditions. The
electron rich heterocycles 1s and 1t produced excellent yields
of allene along with small amounts of diene. Transformation of
protected pyrrole 1u gave only a small amount of allene,
partially due to deprotection under the reaction conditions. 1v,
which is similar to 1a, was converted into the allene 2v in
excellent yield and selectivity. Indole 1w gave only moderate
yields and lacked selectivity. trans-Cinnamon aldehyde was
found to give moderate yields with a small contamination from
3x. Aside from ethyl glyoxalate 1y, which resulted in 29% 2y
without any 3y, other aliphatic aldehydes did not give a
significant amount of allene products. Aliphatic carbonyl
compounds, in general, were found to be low-yielding and
unselective in the described reaction with chloroprene
Grignard.
Table 1. Optimization of the Chloroprene Grignard
Addition towards Homoallenyl Alcohol Selectivity
a b
,
entry
116
2
3
temp
rt
−78 °C
−78 °C
−78 °C
additive
yield
2a
3a
73
99
95
98
1.6
5.7
6.7
1
1
1
1
BDMAEE (1 equiv)
BDMAEE (2 equiv)
4
>20
1
a
The ratio of isomers 2:3 was determined from the crude H NMR.
b
Isolated yield.
Taking into consideration that different parameters and
additives, such as neutral or anionic ligands, are capable of
impacting the reactivity and selectivity of Grignards,18 we
conducted a screening of different additives and reaction
conditions to favor allene formation (Table 1).19 A 2 equiv
portion of of bis[2-dimethylaminoethyl]ether (BDMAEE), a
well-known additive for decreasing Grignard reactivity by
coordination,20 as well as a reaction temperature of −78 °C,
gave the allene 2a in excellent yields, while the formation of
undesired 3a was suppressed almost entirely (entry 4).
For this reaction, different aromatic aldehydes were tested
(Scheme 1). It was found that a slight excess of Grignard and
Substituted chloroprene Grignards were synthesized and
tested in the reaction with aldehydes (Scheme 2). Compound
Scheme 1. Scope for the Chloroprene Grignard Addition to
Different Aldehydes
a b
,
Scheme 2. Addition of Substituted Chloroprene Grignards
a b
,
to Different Aldehydes
a
b
a
b
Combined yield. The ratio of isomers 2:3 is shown after the yield
Major product is depicted showing the combined yield. The ratio of
c
1
1
and is determined from the crude H NMR. Grignard (1.0 equiv),
BDMAEE (2.0 equiv).
isomers 4:5, shown after the yield, is determined from the crude H
NMR. BDMAEE (4.0 equiv) was used.
c
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a
4a was obtained in excellent yield and selectivity from
benzaldehyde (1a). With the encouragement from these
results, challenging substrates 1h and 1x were transformed
into 4b and 4c in excellent allene selectivity. In contrast to
unsubstituted chloroprene Grignard, aliphatic allenes 4d and
4e were obtained in good yields and excellent selectivity.
Following the standard procedure, 1,1,3,3-tetrasubstituted
allenes 4f and 4g were synthesized in excellent yield and
selectivity, with the latter demonstrating compatibility with
aliphatic aldehydes. Synthesis of the 3,3-substituted allene 4h
required 4.0 equiv of BDMAEE to push selectivity to almost
exclusive allene formation.
Scheme 4. Follow-Up Reactions for Homoallenyl Alcohols
While the positive impact of BDMAEE for the selectivity in
the chloroprene Grignard addition to aldehydes has been
clearly demonstrated, the role of the additive in the reaction
remains unconfirmed. Da20b and Wang20d assigned BDMAEE
the role of a chelating ligand for magnesium to form the
intermediates I-1, I-2, and I-3 from the Schlenk equilibrium.
As a consequence, the overall reactivity is decreased, primarily
due to the reduced catalytic potential of MgCl2 (Scheme 3).
a
Reaction conditions: (a) DMP (1.1 equiv), DCM, 0 °C to rt, 16 h,
86%; (b) SOCl2 (1.05 eqiv), CHCl3, rt, 12 h, 85%; (c) PBr3 (1.05
equiv) CHCl3, rt, 18 h, 68%; (d) NaH (1.2 equiv), CS2 (1.5 equiv),
MeI (2.0 equiv), DCM, −78 °C to rt, 2 h, then NaH (1.2 equiv), rt,
16 h, 66%; (e) nBu3SnH (2.5 equiv), AIBN (17 mol %), DCM, 60
°C, 3 h, 57%; (f) PPh3 (1.2 equiv), (PhO)2P(O)N3 (1.2 equiv),
DIAD (1.2 equiv), THF, 0 °C to rt; then (g) PPh3 (1.5 equiv), THF/
water (2:1), rt, 16 h, 45% in two steps; (h) PPh3AuCl (5.0 mol %),
AgSbF6 (5.0 mol %), toluene, rt, 1 h, 90%.
Scheme 3. Proposed Mechanism
Further studies aim to expand the applicability of the
chloroprene Grignard addition to different electrophiles and to
develop an asymmetric version of this reaction.
The decrease in reaction rates21 and better differentiation of
competing transition states22 lead to the observed increase of
selectivity. In accordance with recent studies,22c a six-
membered transition state I-4 is proposed that results in
selective allene formation by allylic addition.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00527.
■
sı
Synthetic procedures for new compounds and their
analytical data (PDF)
Finally, substrates 2a and 4h were subjected to different
follow-up reactions (Scheme 4). Selective oxidation with DMP
gives ketone 6. Chlorination with SOCl2 or bromination with
PBr3 afforded halides 7 and 8 in good yields. From the
procedure reported by Barton and McCombie, deoxygenation
was achieved leaving the allene functionality intact.23 The
transformation of the alcohol group into amine 10 was
achieved by the Mitsunobu reaction towards the corresponding
azide, which is followed by Staudinger reduction to the primary
amine 10. A gold-catalyzed cycloisomerization of 4h according
to Krause yielded dihydropyran 11 in 90% yield.24
Furthermore, our group previously described methods that
employ the alcohol group for the formal diastereoselective
introduction of an amine3 or alcohol4 group, leading to the
valuable syn-allylic alcohol 12 or the aminoalcohols syn- and
anti-13.
AUTHOR INFORMATION
Corresponding Author
■
Bernhard Breit − Institut fur Organische Chemie, Albert-
̈
Ludwigs-Universität Freiburg, Freiburg 79104, Germany;
orcid.org/0000-0002-2514-3898; Email: Bernhard-
breit@chemie.uni-freiburg.de
Author
Arne G. A. Geissler − Institut fur Organische Chemie, Albert-
̈
Ludwigs-Universität Freiburg, Freiburg 79104, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00527
In summary, we successfully developed a cheap, facile, and
high-yielding method for the synthesis of homoallenyl alcohols
and substituted homoallenyl alcohols from abundant aromatic
aldehydes and the chloroprene-derived Grignard reagents. The
obtained racemic homoallenyl alcohols were demonstrated to
be further modified easily and therefore allow access to
structural motives that are far more difficult to obtain following
classical procedures.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the DFG and Fonds der
Chemischen Industrie. The analytical department, in particular
Dr. Manfred Keller, is acknowledged for help in structural
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determination. For their assistance in preparative work, we
thank Mohammad Javad Nisi Asl as well as Lenard Saile.
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