Carreira alkynylations with paraformaldehyde. A mild and convenient protocol for the hydroxymethylation of complex base-sensitive terminal acetylenes via alkynylzinc triflates

Article abstract of DOI:10.1021/ol503222j

A new synthetic protocol for the hydroxymethylation of terminal acetylenes is described that involves stoichiometric Carreira alkynylation with solid paraformaldehyde (HO[CH₂O]_nH) in PhMe at 60 °C. Significantly, the method can be su

Full text of DOI:10.1021/ol503222j

Letter
pubs.acs.org/OrgLett
Carreira Alkynylations with Paraformaldehyde. A Mild and
Convenient Protocol for the Hydroxymethylation of Complex Base-
Sensitive Terminal Acetylenes via Alkynylzinc Triflates
Karl J Hale,* Ziyue Xiong, Liping Wang, Soraya Manaviazar, and Ryan Mackle
The School of Chemistry & Chemical Engineering and the Centre for Cancer Research and Cell Biology (CCRCB), The Queen’s
University Belfast, Stranmillis Road, Belfast BT9 5AG, Northern Ireland, UK
*
S Supporting Information
ABSTRACT: A new synthetic protocol for the hydroxyme-
thylation of terminal acetylenes is described that involves
stoichiometric Carreira alkynylation with solid paraformalde-
hyde (HO[CH O] H) in PhMe at 60 °C. Significantly, the
2
n
method can be successfully applied on acetylenes that possess
base-sensitive ester functionality and heterocyclic rings that
readily undergo metalation. While N-methylephedrine (NME)
is generally the best Zn(OTf) -coordinating ligand for
2
promoting hydroxymethylation, TMEDA can serve as a
replacement.
key requirement of many complex molecule total syntheses
alkyne must also have high water solubility and a low molecular
weight for success. In some instances, high pressure is
additionally needed for the forward reaction to proceed, as was
A
is the hydroxymethylation of a terminal acetylene to obtain
1
the corresponding primary propargylic alcohol. Yet, despite this
6
being a reaction of widely acknowledged synthetic importance,
no truly general method presently exists for implementing it in
good yield, nondestructively, on base-sensitive substrates that
possess either ester or amide functionality or readily metalated
aromatic heterocyclic ring systems.
found by Reppe, in his now classical synthesis of 1,4-dihydroxy-
2-butyne for BASF. Here, copper carbide (Cu C ), acetylene,
2
2
and aqueous formaldehyde were reacted at 100 °C and 5 atm
pressure, in the presence of a catalyst formed from roasted CuO
and Cu(NO ) . Despite the outstanding success of the Reppe
3
2
The most commonly used protocol for the hydroxymethyla-
tion of a terminal acetylene involves deprotonation with an
process, the Cu-mediated hydroxymethylation of terminal
alkynes often performs poorly when applied on complex,
water-insoluble alkynes.
1
,2
organolithium base at low temperature
or with ethyl-
3
magnesium bromide in an ethereal solvent at reflux or with
Of the more recent effective synthetic methods that have
4
sodium amide in liquid NH . The resulting metal acetylide is
emerged for complex terminal acetylene hydroxymethylation,
3
7a
then reacted with gaseous HCHO or solid paraformaldehyde
Floreancig’s adaption of Negishi’s elegant 1,1-disubstituted
7b
(
HO[CH O] H) (n = 4−100). In some instances, 1,3,5-trioxane
enol phosphate elimination method is a particularly note-
worthy and powerful contribution. It uses LDA in THF at −78
°C to fashion the desired lithium acetylide, which is thereafter
reacted with solid paraformaldehyde at reflux. The latter protocol
complements the much earlier dibromoalkene to lithium
2
n
2c
is employed as the electrophile but, according to Brandsma,
,3,5-trioxane is generally not a competent electrophile for this
1
process, and consequently, it is rarely used. Despite the excellent
performance of the aforementioned HCHO gas or solid
paraformaldehyde alkyne hydroxymethylation methods, none
of them can be productively applied on terminal acetylenes that
contain base-sensitive functionality of the type mentioned above,
which means that there is a major methodological gap in our
current synthetic arsenal.
8
acetylide conversion of Corey and Fuchs, which also relies on
an in situ generated lithium acetylide/HCHO trapping to achieve
1a
its goal. Yet another much less commonly employed procedure
for terminal acetylene hydroxymethylation is the electrolysis of
an alkyne with paraformaldehyde and Et NOTs in DMF, using a
4
−2
9
While less basic monosubstituted copper acetylides have been
found to react with aqueous HCHO, they must be generated
Pt cathode at 3.3 mA cm . The reaction of monoalkyl
acetylenes with 10 mol % of Me N(Bn)OH (TRITON B) and
3
5
10
with freshly prepared CuOH, and high reaction temperatures
paraformaldehyde in DMSO is another published method for
are often necessary to achieve even a quite modest conversion
into the corresponding primary alcohol (eq 1). In most cases, the
the hydroxymethylation of a terminal acetylene, but frequently
this protocol is low yielding when applied on complex terminal
acetylene substrates, and it is, of course, totally incompatible
10b
Received: November 5, 2014
©
XXXX American Chemical Society
A
DOI: 10.1021/ol503222j
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
with the presence of labile esters. Although CsOH, Sn(OTf) /
Letter
11
2
Table 1. A New, Mild Hydroxymethylation Procedure for
1
2
13
14
Et N, ZnCl /Et N, KOBu-t, cat. RuCl /cat. In(OAc) /
Terminal Alkynes in PhMe
3
2
3
3
3
1
5
16
morpholine, and GaI /Et N have all been reported to afford
3
3
metal acetylides that react readily with aldehydes, it is striking to
note that paraformaldehyde or gaseous HCHO are always absent
from the lists of viable reaction partners that are presented. The
same is true for all asymmetric alkynylation processes that have
17
so far been described and while, admittedly, this dearth of
reports might simply be due to gaseous HCHO or solid
paraformaldehyde never having been evaluated in this capacity,
equally well, it could be due to these electrophiles simply not
performing successfully in these processes.
In this regard, solid paraformaldehyde (HO[CH O] H)
2
n
(
where n = 4−100) has long been known to cause problems
for certain metal acetylide trappings, due to the fact that it is
formally a diol polycondensation product of methylene glycol. As
such, it has considerable potential to quench alkynyl anions to a
very significant degree. Consequentially, dry gaseous HCHO is
often used in such couplings, and technically, on large scale, such
reactions are often difficult to perform safely.
Given all of these problems, there is a pressing need for new,
more convenient, reaction technologies that will allow the
efficient hydroxymethylation of a wide range of structurally
diverse, water-insoluble alkynes with solid paraformaldehyde
under mild conditions, most especially alkynes with base-
sensitive groups. In this regard, we recently became interested in
synthesizing the monosaccharide alkynol derivatives 2, 4, and 6
18
(
Table 1) for evaluation as hydrostannation models and
synthetic probes for a projected future TMC-171C total
1
9
synthesis. However, the direct preparation of propargyl
alcohols 2 and 4 from the O-acetylated glycosides 1 and 3 did
not look feasible using existing established methods because n-
BuLi, EtMgBr, or LDA would all adversely damage the acetate
esters present in these two substrates. n-BuLi and LDA might
also cause fragmentation of the dioxolane acetal in 5 due to O-
glycoside-directed metalation at C(3) and attendant E1cb
elimination, a reaction known to proceed with facility for 2,3-
20
dioxolane benzylidene acetals of α-D-mannopyranosides.
After giving the problem some careful thought, we eventually
decided to investigate whether a hitherto-undescribed Carreira
2
1
alkynylation with solid paraformaldehyde might prove useful in
this capacity, and herein, we now report that this new
hydroxymethylation protocol works eminently well. Not only
does it allow for a direct preparation of the O-acetylated
glycosides 2 and 4, it also permits the hydroxymethylation of a
wide range of other alkynes with base-sensitive aromatic
heterocycle functionality, molecules which ordinarily would
undergo competing metalation and hydroxymethylation at other
sites if attempted with bases such as n-BuLi, EtMgBr, or LDA. As
a consequence, we have now provided the first truly general
solution to the issue of base-sensitive terminal acetylene
hydroxymethylation with solid paraformaldehyde.
The first alkyne that we examined in this way was the glycoside
1
(Table 1), and since we had recently successfully used a
21
catalytic Carreira asymmetric alkynylation procedure in our
18b
total synthesis of (−)-(3R)-inthomycin C, we initially decided
to evaluate these reaction conditions. This entailed us stirring 0.4
equiv of (−)-N-methylephedrine (NME), 0.3 equiv of Zn-
for alkyne 3, under identical circumstances, except here the
reactants were heated at 60 °C with 5 equiv of paraformaldehyde
for 20 h. This lack of reaction progress in both catalytic cases
(OTf) , and 1 equiv of Et N in PhMe at rt for 2 h, adding 1,
2 3
21
stirring at rt for 20 min, to enable initial metalation to proceed,
and then heating the reactants at 60 °C with 1 equiv of
paraformaldehyde for 4 d. Unfortunately, these conditions led to
little noticeable reaction to give 2. A similar outcome was found
eventually led us to try Carreira’s stoichiometric procedure on
1. This involved us stirring a THF solution of 1.7 equiv of
(−)-NME with 1.6 equiv of Zn(OTf) and 1.7 equiv of Et N for 2
2
3
18c
h, adding 1.5 equiv of alkyne 1, and continuing stirring for 20
B
DOI: 10.1021/ol503222j
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Organic Letters
Letter
24b
min before adding 1 equiv of paraformaldehyde. Once more, the
alkynylation reaction did not proceed satisfactorily at rt.
Significantly though, when the reactants were subsequently
heated at 60 °C for 14 h, the desired product 2 did start to form,
but not in a very clean way. We therefore repeated the reaction
on 100 mg scale with respect to 1 (1 equiv), using 1.1 equiv of
accessed. Even so, we have still attempted to find a much
cheaper commercial alternative to NME that works in a near
equivalent way. Our screening has revealed that TMEDA can
often serve as a reasonably effective and viable replacement for
NME in such applications (Scheme 1). Thus, when our
(
−)-NME, 1.1 equiv of Zn(OTf) , 1.1 equiv of Et N, and 1 equiv
Scheme 1. TMEDA/Zn(OTf) /Et N-Mediated Alkyne
Hydroxymethylation
2
3
2
3
of paraformaldehyde, except now we conducted the reaction
exclusively in PhMe at 60 °C for 6 h. Thereafter, the alkynol 2
was formed cleanly, but only in 29% yield. Wondering whether
this lack of reaction progress might simply be due to the
difficulties of stirring the biphasic reaction mixture well on small
scale, we repeated the reaction with 0.5 g of the alkyne 1 in a
greater volume of PhMe. Significantly, the extent of conversion
was now much better, and once more, alkynol 2 formed cleanly,
but in a greatly improved 65% yield. Following several further
rounds of optimization, it was eventually discovered that vigorous
stirring of 2 equiv of (−)-NME, 1.9 equiv of Zn(OTf) , and 2
2
equiv of Et N in dry PhMe at rt for 2 h under N produced a
3
2
biphasic mixture that went on to react cleanly with 1 equiv of the
alkyne 1. Moreover, when these reactants were stirred at rt for 20
min, and subsequently reacted with 1 equiv of paraformaldehyde
at 60 °C over 2 h, 2 was obtained very cleanly in 81% yield on 1 g
scale (Table 1). The same reaction was also conducted with
Zn(OTf) /TMEDA/Et N/paraformaldehyde conditions were
2 3
applied to 19 in PhMe at 60 °C for 1.5 h, 20 was formed in 61%
yield with its methyl ester intact. The yield of this reaction
certainly compared favorably with the 64% yield obtained by the
(−)-NME-mediated method and, once again, the heterocyclic ring
did not undergo competing metalation and concomitant hydrox-
ymethylation.
(+)-NME to equal effect, showing that both enantiomers of NME
work equivalently in these reactions with chiral substrates of this sort.
Next, we applied our (−)-NME conditions to the but-3-ynyl β-
Indeed, in the case of alkyne 11, the TMEDA ligand actually
2
2
D-galactopyranoside 3 and the but-3-ynyl 2,3;4,6-di-O-
isopropylidene α-D-mannopyranoside 5 (Table 1) and again
found that the desired propargyl alcohols 4 and 6 were formed
cleanly in 84% and 82% yield on 0.57 and 1 g scale, respectively.
While these conditions worked extremely well for each of these
three substrates, and many others besides, a further increase in
the amount of paraformaldehyde (5 equiv) and a longer reaction
time did prove necessary to coax the optimal yield from the more
outperformed (−)-NME in the Zn(OTf)
2 3
/Et N-mediated
terminal alkyne hydroxymethylation process in PhMe, cleanly
2
d,25
affording the known 12
in 78% yield after 3 h at 60 °C.
Even so, one undesired side-reaction that did come to light,
when we examined the carbohydrate alkynes 1 and 3 in the
Zn(OTf) /TMEDA/Et N process, was competing O-acetyl
2 3
transfer to the alkynol products 2 and 4, which occurred
alongside hydroxymethylation (Scheme 2). This was not a
serious issue in the NME-mediated processes.
18a
hindered terminal alkyne 7 which possesses multiple bulky
protecting groups in close proximity to the acetylene. Of special
note, however, was our discovery that the optimized
hydroxymethylation conditions could be productively applied
Scheme 2. O-Acetyl Transfer during TMEDA/Zn(OTf)2/
Et N-Mediated Hydroxymethylation of Alkynes 1 and 3
3
23
with high regioselectivity on each of the readily metalated
heterocyclic alkynes 13, 15, 17, 19, and 21 (Table 1), without the
2
3
occurrence of undesired competing deprotonation and
hydroxymethylation of their heterocyclic rings or the methyl
side chain in the case of 21. This outcome, along with survival of
the ester functionality in 2, 4, 18, and 20, was particularly striking.
The lack of O(1)-directed C(3)-metalation and E1cb acetal
2
0
elimination in the di-O-isopropylidenated mannopyranoside 5
is another item of note.
The lowest yield that we have so far encountered is with the
1
8d
acetylene 9, a substrate that we could not optimize further due
to the dearth of starting material presently available. Never-
theless, the hydroxymethylation did proceed very cleanly, which
is contrary to what the 31% yield of 10 might at first suggest.
In this regard, we have found that the best yields generally
accrue when these hydroxymethylations are conducted on larger
scale (>0.4 g alkyne), where more efficient mixing of the biphasic
reaction mixtures can often be achieved. Saying this, we have
successfully conducted several experiments on quite small scale
and obtained decent yields (see Table 1).
A detailed study of the Zn(OTf) /Et N-mediated hydrox-
ymethylation of alkyne 11 with the alternate achiral ligand,
2
3
(dimethylamino)ethanol (Me NCH CH OH), in place of
2
2
2
(−)-NME, under our standard conditions, demonstrated that
while this system does indeed provide the desired alkynol 12 very
cleanly, it does so only in low yield (26%) (Scheme 3). In fact, the
reaction does not reach completion even after it is heated for 7 d
at 60 °C. Although 1-(N,N-dimethylamino)-2-propanol per-
forms better as a ligand in this system, alkyne hydroxymethy-
lation is still extremely slow, with 12 only being produced in 31%
yield after the reaction has been heated at 70 °C for 65 h.
Given that the rate of alkyne hydroxymethylation is greatly
diminished when Me NCH CH OH or Me NCH CH(Me)OH
Given the current quite high cost of commercially purchased
−)- and (+)-NME for university research, we draw attention to
the fact that both antipodes can be readily synthesized cheaply on
(
2
2
2
2
2
24a
large scale by the method of Smith; the racemate is also easily
is employed, we suspect that these sterically less encumbered
C
DOI: 10.1021/ol503222j
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
5) Heilbron, I. M.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947,
Scheme 3. Use of Me NCH CH OH and
2
2
2
1
586.
6) Baptista, R. J. Walter Reppe: Pioneer in Acetylene Chemistry, 2009,
http://www.colorantshistory.org/ReppeChemistry.html (accessed Dec
, 2014).
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E.; King, A. O.; Klima, W. L.; Patterson, W.; Silveira, A., Jr. J. Org. Chem..
980, 45, 2526.
Me NCH CH(Me)OH as Ligands
2
2
(
9
(
1
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(9) Torii, S.; Okumoto, H.; Kiyoto, T.; Hikasa, S. Chem. Lett. 1988,
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977.
(10) (a) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.;
Saito, S. J. Org. Chem. 2003, 68, 3702. (b) Molino, B. F.; Yang, Z. US
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ligands are causing extremely stable trimeric alkynylzinc alkoxide
(
(
11) Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463.
12) Yamaguchi, M.; Hayashi, A.; Minami, T. J. Org. Chem. 1991, 56,
2
6
complexes to form which, thereafter, are unable to readily
dissociate into the monomeric alkynylzinc reagents needed to
engage in nucleophilic addition. By way of contrast, when much
more sterically crowded NME ligands are employed, these
probably form less tightly associated dimeric alkynylzinc alkoxide
4
(
091.
13) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2002, 43, 8323.
(14) Wang, S.-H.; Tu, Y.-Q.; Chen, P.; Hu, X.-D.; Zhang, F.-M.; Wang,
A.-X. J. Org. Chem. 2006, 71, 4343.
(15) Wei, C.; Li, C.-J. Green Chem. 2002, 4, 39.
2
6
complexes that have a much greater tendency to dissociate into
nucleophilically competent acetylenic anion monomers. These
arguments, which are based on Noyori and Kitamura’s work on
(
(
16) Han, Y.; Huang, Y.-Z. Tetrahedron Lett. 1995, 36, 7277.
17) Review: Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351,
26
963 and references cited therein.
18) For the O-directed free radical hydrostannation of propargylically
oxygenated alkylacetylenes with Ph SnH/cat. Et B, see: (a) Dimopou-
aminoalcohol-accelerated dialkylzinc addition to aldehydes,
(
nicely explain why much faster rates of alkyne hydroxymethy-
lation are observed with the privileged Zn(OTf) /NME/Et N
3
3
2
3
los, P.; Athlan, A.; Manaviazar, S.; George, J.; Walter, M.; Lazarides, L.;
Aliev, A. E.; Hale, K. J. Org. Lett. 2005, 7, 5369. (b) Synthesis of (3R)-
reagent ensemble.
Thus, to conclude, a nonpyrophoric way of hydroxymethylat-
ing base-sensitive alkyne substrates has been devised that is
compatible with many commonly used alcohol and amine
protecting groups. Given the broad scope of this reaction, we
expect that it will be employed widely over the coming years.
(
−)-inthomycin C: Hale, K. J.; Grabski, M.; Manaviazar, S.; Maczka, M.
Org. Lett. 2014, 16, 1164. Hale, K. J.; Hatakeyama, S.; Urabe, F.; Ishihara,
J.; Manaviazar, S.; Grabski, M.; Maczka, M. Org. Lett. 2014, 16, 3536. (c)
Synthesis of C(7)−C(22)-sector of (+)-acutiphycin: Hale, K. J.;
Maczka, M.; Kaur, A.; Manaviazar, S.; Ostovar, M.; Grabski, M. Org.
Lett. 2014, 16, 1168. (d) Formal total synthesis of (+)-pumiliotoxin B:
Manaviazar, S.; Hale, K. J.; LeFranc, A. Tetrahedron Lett. 2011, 52, 2080.
27
ASSOCIATED CONTENT
Supporting Information
■
(19) TMC-171C: Kohno, J.; Asai, Y.; Nishio, M.; Sakurai, M.; Kawano,
*
S
K.; Hiramatsu, H.; Kameda, N.; Kishi, N.; Okuda, T.; Komatsubara, S. J.
Antibiot. 1999, 52, 1114.
Full experimental details and spectra for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(20) Horton, D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227.
(21) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2
2
000, 122, 1806. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc.
001, 123, 9687.
AUTHOR INFORMATION
Corresponding Author
■
(22) Bretschneider, H.; Beran, K. Monatsh. Chem. 1949, 80, 262.
(23) (a) For the rapid (30 s) ring deprotonation and trapping of
*
E-mail: k.j.hale@qub.ac.uk.
carboxythiazole methyl esters with LDA/THF at −78 °C, see: Deng, S.;
Taunton, J. Org. Lett. 2005, 7, 299. (b) For the n-BuLi-mediated C2-
deprotonation of N-methylimidazole, see: Nilsson Lill, S. O.; Pettersen,
D.; Amedjkouh, M.; Ahlberg, P. J. Chem. Soc., Perkin Trans. 1 2001, 3054.
Notes
The authors declare no competing financial interest.
(
c) For an excellent review on metallated heterocycles in synthesis, see:
ACKNOWLEDGMENTS
We thank QUB for a starter grant (to K.J.H.) and for
studentships.
■
Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104, 2667.
(24) (a) (+)- and (−)-NME can be readily prepared by N-methylation
of the individual enantiomers of ephedrine with MeI: Smith, S. J. Chem.
Soc. 1927, 2056. Ephedrine is presently priced at £63.10 for 100 g. (b)
For the industrial production of (±)-NME, see: Sugasawa, S.; Yamazaki,
T.; Kawanishi, M.; Iwao, J. Yakugaku Zasshi 1951, 71, 530.
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DOI: 10.1021/ol503222j
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