Chemoselective additions of chloromethyllithium carbenoid to cyclic enones: A direct access to chloromethyl allylic alcohols

Article abstract of DOI:10.1002/adsc.201301042

Chloromethyllithium carbenoid has been chemoselectively added to cyclic enones (5-, 6- and 7-membered systems, including two natural products) to provide chloromethyl allylic alcohols. Under the optimized reaction conditions neither concomitant (n+1) homologation nor conjugate addition or Simmons-Smith-like cyclopropanation takes place. The presence of LiBr is estimated to play a dual role, namely as a carbenoid stabilizer and mild Lewis acid activator of the C=O group. Notably, the mesomeric effect caused by β-heteroatom-containing substituents promotes the attack of the reagent at the most activated position.

Full text of DOI:10.1002/adsc.201301042

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DOI: 10.1002/adsc.201301042
Chemoselective Additions of Chloromethyllithium Carbenoid to
Cyclic Enones: A Direct Access to Chloromethyl Allylic Alcohols
Vittorio Pace,a,* Laura Castoldi,a and Wolfgang Holzera
a
Faculty of Life Sciences, Department of Pharmaceutical Chemistry, Division of Drug Synthesis, University of Vienna,
Althanstrasse 14, A-1090 Vienna, Austria
Phone: (+43)-1-4277-55623; e-mail: vpace@farm.ucm.es
Received: November 21, 2013; Revised: January 20, 2014; Published online: April 15, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301042.
Abstract: Chloromethyllithium carbenoid has been
chemoselectively added to cyclic enones (5-, 6- and
7-membered systems, including two natural prod-
ucts) to provide chloromethyl allylic alcohols.
Under the optimized reaction conditions neither
concomitant (n+1) homologation nor conjugate ad-
dition or Simmons–Smith-like cyclopropanation
takes place. The presence of LiBr is estimated to
play a dual role, namely as a carbenoid stabilizer
and mild Lewis acid activator of the C=O group.
Notably, the mesomeric effect caused by b-heteroa-
tom-containing substituents promotes the attack of
the reagent at the most activated position.
ment in the presence of a lithium base, it is possible
to obtain a homologated a-chloro ketone (III) or
a
simple homologated ketone (II), respectively
(Scheme 1, top).[8c,10] On the other hand, the employ-
ment of monohalomethyllithium carbenoids (e.g.,
Keywords: allylic alcohols; chemoselectivity; chloro
compounds; enones; lithium carbenoids
Cyclic ketones are ubiquitous motifs in nature and
from a synthetic perspective they constitute versatile
building blocks susceptible of multiple transforma-
tions.[1] In particular, the reaction with functionalized
carbon nucleophiles (e.g., sulphur ylides,[2] diazo com-
pounds[3]) has been frequently employed as a useful
strategy to access homologated structures such as ep-
oxides[4] or (n+1) cyclic units.[5] In this sense, such re-
actions constitute effective alternatives to the classic
Tiffeneau–Demjanov reaction[6] which, despite its syn-
thetic potential, is not straightforward provided that it
is a multi-step route.[6d,7] Indeed, in this scenario
a prominent position is occupied by lithium carbenoid
reagents[8] pioneered by Nozaki and co-workers who
developed in the 1970s a series of useful protocols to
access the aforementioned homologated saturated
structures.[9] In these seminal works, they showed that
upon reaction of a cyclic ketone (I) with dihalome-
thyllithium reagents (i.e., LiCHCl2 or LiCHBr2) fol-
lowed by the so-called b-oxido carbenoid rearrange- Scheme 1. Context of the presented work.
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Table 1. Reaction optimization.[a]
Entry
ICH2Cl (equiv.)
RLi (equiv.)
Solvent
Temp. [8C]
Yield of 2 [%][b]
1
2
3
4
5
6
7
8
2.0
3.0
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
MeLi-LiBr (1.5)
MeLi-LiBr (2.5)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi-LiBr (4.0)
MeLi (4.0)
THF
THF
THF
THF
THF
THF
Et2O
MTHF
CPME
Trapp mixture
THF:Et2O
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ70
ꢀ60
ꢀ95
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
62
79
88
71
49
91
84
70
66
80
93
35
9
10
11
12
[a]
Reactions time: 1 h.
Isolated yields.
[b]
LiCH2X)[11] in analogous processes has been practical-
In this work, we disclose a chemoselective 1,2-addi-
ly limited to the formation of epoxides starting from tion of LiCH2Cl to cyclic enones. Significantly, under
saturated cyclic ketones,[12] leaving almost unexplored the optimized reaction conditions, it is possible to
in-depth investigations on their reactivity with multi- access exclusively the adduct arising from the addition
functionalized structures such as a,b-unsaturated of the carbenoid to the most activated carbon atom of
(cyclic) ketones.[13] In the course of a currently ongo- the cycle thus, providing an easy access to tertiary
ing project in our group focused on the use of such re- cyclic allylic alcohols without any contaminating side-
agents for the homologation of electrophilic sub- product such as epoxides or homologated ketones.
strates such as carboxylic acid derivatives (Weinreb This procedure has been applied to five-, six- and
amides/esters)[14] and isocyanates,[15] we have been at- seven-membered enones including fused natural prod-
tracted by the possibility to access cyclic allylic alco- ucts structures. The reaction is tolerant to sensitive
hols incorporating at the quaternary carbon a reactive olefins and/or other functionalities susceptible to car-
chloromethylenic group. Although conceptually benoids. A mechanistic explanation of the different
simple, the envisaged synthetic operation had to con- behaviors towards the reagents displayed by b-oxo-,
sider the possible decomposition pathways which can b-thio- and b-aza-type substituted cyclic enones is
occur on the Tiffeneau–Demjanov-type tetrahedral provided.
intermediate (V, Scheme 1, bottom): a) the transfor-
As the model reaction we selected the challenging
mation into the homologated ketone of type VII by enone 1 bearing two conjugated olefinic moieties and
expulsion of the halogen atom and transposition – in thus, susceptible not only to cyclopropanation but
analogy to diazomethane-based ring enlargement op- also to 1,4- or 1,6-conjugate additions, which have
erations;[16] b) the ring closure via an internal dis- been previously observed with carbenoid reagents.[21]
placement of the chlorine atom carried out by the Upon generation of the LiCH2Cl carbenoid in the
highly nucleophilic lithium alkoxide to give the corre- presence of 1 through the reaction of MeLi-LiBr
sponding epoxide (VIII), similarly to Corey–Chay- (1.5 equiv.) with ICH2Cl (2.0 equiv.) it was possible to
kovsky processes.[2a,5b,17] In addition, c) in the case of obtain the chlorohydrin 2 in a satisfactory 62% yield
enones like vinylogous carboxylic acid triflates (IV after 1 h (Table 1, entry 1). By increasing the amount
with R=OTf), the possibility exists to promote highly of carbenoid up to 4 equiv., the desired product could
efficient tandem nucleophilic addition–fragmentation be obtained in an excellent 88% yield without need-
reactions to provide alkynyl ketones IX, as recently ing to perform any additional purification (entry 3).
exploited by Dudley and co-workers[18] as an alterna- Raising the temperature up to ꢀ608C resulted in de-
tive to Eschenmoser–Tanabe processes.[19] Finally, we creased yields (entries 4 and 5), whereas at ꢀ958C
considered as another possible shortcoming the inher- only a minimal gain was observed (entry 6). Thus, per-
ent known tendency of lithium carbenoids to promote forming the reaction at ꢀ788C constitutes a good
cyclopropanation-type reactions with olefins.[20]
compromise between an easy experimental feasibility
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Chemoselective Additions of Chloromethyllithium Carbenoid
Table 2. Effect of additives on the chloromethylation of
cyclic enone 1.[a]
and reaction efficiency. The solvent effect was also
noticeable: we observed that a 1:1 v/v mixture of
THF and diethyl ether maximizes the yield (entry 11)
compared to media constituted by these solvents not
mixed (entries 3 and 7) or by the use of the Trapp
mixture[22] (THF:Et2O:n-pentane, 2:2:1, v/v) which is
frequently employed in organometallic reactions
(entry 10). Analogously, the formation of the highly
sensitive carbenoid species is significantly decreased
in non-optimal coordinating solvents such as 2-meth-
yltetrahydrofuran[23] (MTHF, entry 8) and cyclopentyl
methyl ether (CPME, entry 9).
Notably, the presence of a mild Lewis acid such as
LiBr is crucial for the successful outcome of the reac-
tion. Indeed, it is now well established that such a salt
stabilizes the carbenoid species by preventing its de-
composition into a carbene through a coordinative
effect with LiCH2Cl.[12a,24] However, by generating the
latter (4 equiv.) in the absence of LiBr (i.e., use of
simple MeLi ethereal solution), compound 2 could be
obtained in only 35% yield after 1 h (entry 12). This
somewhat surprising result prompted us to run a con-
trol experiment in the presence of a Weinreb amide
(3) which, as we reported recently,[14] is known to
react with this carbenoid (Scheme 2). Thus, by treat-
Entry
Additive
Equiv.
Yield of 2 [%][b]
1
2
3
4
5
6
7
8
LiBr[c]
4.0
4.0
0.2
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
93
82
74
68
75
72
77
74
66
69
64
LiBr[d]
LiBr[c]
MgBr2
MgBr2-etherate
MgI2
Mg
Mg
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
10
11
ZnBr2
ZnI2
ZnACTHNUTRGENUG(N OTf)2
[a]
Reaction time: 1 h.
Isolated yields.
From MeLi-LiBr ethereal solution.
Added as a powder.
[b]
[c]
[d]
ing an equimolar mixture of 1 and 3 with LiCH2Cl we (20 mol%, entry 3) resulted in a lower yield. Subse-
could isolate chlorohydrin 2 and chloro ketone 5 in quently, we screened other known Lewis acids such as
31% and 65% yields, respectively. Based on this MgBr2, MgBr2-etherate, MgI2, Mg
ACHTUTGNRNENUG(ClO4)2, MgACHTUNGTRENNUNG(OTf)2,
result, we concluded that although the generation of ZnBr2, ZnI2, Zn(OTf)2 (entries 4–11) and confirmed
AHCTUNGTRENNUNG
the carbenoid is not maximized (for the lack of the that LiBr is the best one for the purpose. Presumably
coordinating effect of LiBr) its formation is still effec- these salts can also act by generating Mg or Zn carbe-
tive and thus, the beneficial activity of the bromide noids[25] through in situ transmetallations and thus,
should be found predominantly in its mild Lewis lowering the nucleophilicity of the carbenoid-type
acidic activating effect towards the carbonyl of the species.
enone.
With the optimized conditions in hand, we next
Subsequently, we observed that the generation of turned our attention to the scope of the reaction
the carbenoid through the slow addition (5 min) of (Scheme 3). Interestingly, it could be applied to differ-
MeLi-LiBr complex to the solution of ICH2Cl per- ently sized ring systems, thus providing cyclopentene
forms better than the addition of simple MeLi solu- (6a, b), cyclohexene (6c–g) and cycloheptene (6h) de-
tion to a mixture of ICH2Cl and LiBr (Table 2, en- rivatives bearing different substituents across the
tries 1 and 2). As a further confirmation of the pivotal cyclic core. Pleasingly, the protocol tolerates function-
double role of LiBr (carbenoid stabilizer and carbonyl alities sensitive to organolithiums such as a chlorine
activator), the use of a substoichiometric amount atom (5f!6f) or even the bicyclic acetal-type system
of levoglucosenone (5i!6i), a cellulose-derived cyclic
enone, which is frequently employed as versatile scaf-
fold in synthetic medicinal chemistry.[26] Unfortunate-
ly, although compound 6i was obtained as a single dia-
stereoisomer, no stereochemical proof could be de-
duced by NOE experiments (see the Supporting In-
formation). The presence of heteroatoms in the start-
ing enones is permitted, thus providing chlorohydrins
6j and 6k in high yields. The reactive olefinic moiety
can also be included into an aromatic system as evi-
denced in the case of compound 6l resulting from flu-
orenone 5l: it should be noted that the carbenoid,
under the reaction conditions, does not display any
electrophilic reactivity towards the aromatic rings of
Scheme 2. Control experiment in the presence of a Weinreb
amide: study of the effect of LiBr.
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single diastereoisomers showing a stereochemistry at
the newly formed quaternary center as depicted in
Scheme 3 (6m, 6n).
Of particular significance is the presence of an elec-
tron-releasing oxygen atom at the b-position of the
olefinic bond which, formally transforms the enone
systems 7 and 8 into masked 1,3-dicarbonyl deriva-
tives (Scheme 4).[29] The resulting mesomeric effect, as
showed by the canonic forms 7a/7b and 8a/8b, evi-
dently allows the attack of the carbenoid at such (acti-
vated) positions with formation of intermediates 7c
and 8c, respectively. The nature of the group linked
to the enol-type oxygen atom plays a pivotal role in
determining the mechanism for the collapse of the ad-
dition intermediates of type c. Thus, in the presence
of nucleofugal leaving groups (e.g., EtO or MsO)
which could be easily eliminated, upon quenching the
enone system is re-established providing compound 9
as the sole reaction product in 84% isolated yield.
On the other hand, in the case of chromone 10 the
carbenoid addition takes place simili modo on the
(activated) b-C-atom of the enone system, thus af-
fording the intermediate 10c. The latter evidently
does not possess any (nucleofugal) leaving group and,
as a consequence, the acidic treatment of this enolate
could only restore the ketone form thus, giving the
substituted chromanone 11 in 80% yield. It is worth
observing the difference in reactivity between the
masked 1,3-dicarbonyl compounds and b-chloroenone
5f: in this latter case, the impossibility to conjugate
the lone-pair of chlorine with the enone system, ac-
counts for the direct 1,2-addition.
It is worth noting the different outcome of the reac-
tion involving a b-oxo species (compounds 7, 8, 10,
Scheme 4 and Scheme 5) and the corresponding b-
thio analoge 5j (Scheme 3). As shown in Scheme 6,
we explain this behavior based on the lower ability
(compared to oxygen) of the molecular orbital of the
Scheme 3. Scope of the reaction[28]
.
this latter substrate. Remarkably, the methodology sulphur atom to overlap with the adjacent carbon. As
could be efficiently applied to complex enone systems a consequence, in the case of oxygen the attack of the
incorporated into natural products such as nootkatone carbenoid can be explained considering the larger
(5m), a sesquiterpene derived from grapefruit with in- contribution of canonic form B, while in the case of
secticide-repellent properties towards deer ticks.[27] sulphur the correspondent form D is less favored.
With much of our delight we prepared the medicinal- Similarly, the electron-withdrawing effect of a Boc
ly relevant scaffold 6n from cholest-4-en-3-one (5n) in group on the nitrogen atom of a 4-piperidone (i.e.,
high yield, thus showcasing the possibility to expand compound 5k) also reduces the extent of overlapping
the use of such chemistry to non-academic audiences. in structure F, thus favoring the attack via an 1,2-fash-
Pleasingly, both these products were obtained as ion.
Scheme 4. b-Activating effect of an RO group: the case of 3-alkoxy systems.
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Chemoselective Additions of Chloromethyllithium Carbenoid
Scheme 5. b-Activating effect of an RO group: the case of chromone.
a solution of MeLi-LiBr complex (1.5M, 2.67 mL, 4.0 mmol,
4.0 equiv.) during 5 min. The mixture was stirred for 1 addi-
tional hour before it was quenched with saturated aqueous
NH4Cl (2 mL) and extracted with Et2O (3ꢁ5 mL). The or-
ganic layer was washed with brine (5 mL), dried over
Na2SO4, filtered and after removing the solvent under re-
duced pressure, analytically pure chlorohydrin 2 was ob-
tained as a colorless oil; yield: 231 mg (93%). Full experi-
mental details including characterization of the compounds
1
and copies of H NMR and 13C NMR spectra are available
in the Supporting Information.
Acknowledgements
The authors thank the University of Vienna for financial sup-
port. One of the authors (L.C.) acknowledges the University
of Vienna for a predoctoral Uni:docs fellowship.
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