Direct, Mild, and General n-Bu4NBr-Catalyzed Aldehyde Allylsilylation with Allyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.7b03193

A direct, mild, and general method for the enantioselective allylsilylation of aldehydes with allyl chlorides is reported. The reactions are effectively catalyzed by 5 mol % of n-Bu₄NBr, and this rate acceleration allows the use of complex allyl donors in fragment-coupling reactions and of electron-deficient allyl donors. The results are (1) significant progress toward a "universal" asymmetric aldehyde allylation reaction that can reliably and highly stereoselectively couple any allyl chloride-aldehyde combination and (2) the discovery of a novel mode of nucleophilic catalysis for aldehyde allylsilylation reactions.

Full text of DOI:10.1021/acs.orglett.7b03193

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Direct, Mild, and General n‑Bu4NBr-Catalyzed Aldehyde
Allylsilylation with Allyl Chlorides
Makeda A. Tekle-Smith,† Kevin S. Williamson,† Isaac F. Hughes, and James L. Leighton*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: A direct, mild, and general method for the
enantioselective allylsilylation of aldehydes with allyl chlorides is
reported. The reactions are effectively catalyzed by 5 mol % of n-
Bu4NBr, and this rate acceleration allows the use of complex allyl
donors in fragment-coupling reactions and of electron-deficient allyl
donors. The results are (1) significant progress toward a “universal”
asymmetric aldehyde allylation reaction that can reliably and highly
stereoselectively couple any allyl chloride_aldehyde combination and
(2) the discovery of a novel mode of nucleophilic catalysis for aldehyde allylsilylation reactions.
espite major progress on effective methods for highly
D
stereoselective aldehyde allylation1,2 and crotylation3
reactions, including the Krische approach which heretofore
uniquely obviates preformation and isolation of the active
allylmetal(loid) species,4 the full potential of this reaction type
remains unfulfilled. For example, direct fragment coupling
allylation reactions with complex and high MW allyl donors
(e.g., the hypothetical synthesis of the EF half of spongistatin 1 by
way of a direct coupling of (E)-4-chloropenta-2,4-dienal (1) and
complex allyl chloride 2 (Figure 1a)) are essentially unknown.5
More generally, the development of a “universal” Type 16
aldehyde allylation reaction that can directly and efficiently
couple any allyl-X donor in a practical and sustainable way and
with reliably high levels of both efficiency and stereoselectivity
would greatly expand the utility of this reaction type in the
synthesis of a broad array of structurally diverse targets (Figure
1b). Our second-generation allylsilylation methodology7 is
characterized by many of the attributes listed in Figure 1b, but
the scope with respect to the allyl donor is limited to simple low
MW and alkyl-substituted (i.e., electron-rich) allyl fragments by
the requirement for preformation (by way of the Benkeser−
Furuya reaction8,9) and isolation of the allyl trichlorosilanes and
by limited allylsilane reactivity, respectively (Figure 1c). To more
fully realize a “universal” and direct allylation reaction, we set out
to address these serious limitations and report herein that the
critical enabling discovery was that these allylsilylation reactions
are effectively catalyzed by tetrabutylammonium bromide.
At the outset, we were optimistic that the Benkeser−Furuya
reaction could be effectively telescoped10 with the allylation
reaction given that its only byproduct is Et3N·HCl. This turned
out not to be the case, however, as the fully telescoped reaction
with dihydrocinnamaldehyde led to the isolation of the product
in only 34% yield (Table 1, entry 1), a result that may be
attributed to silylchlorohydrin formation (see Figure S1 and
structure F in Figure 4b, below) in direct analogy to the
observations of Denmark in Lewis base-catalyzed reactions of
allyl- and enoltrichlorosilanes with unhindered aliphatic
Figure 1. (a) Hypothetical direct complex fragment coupling allylation
of aldehyde 1 with stereochemically and functionally complex allyl
chloride 2. (b) Desirable attributes of a “universal” and direct aldehyde
allylation reaction. (c) Our allylsilylation method entails preformation
and isolation of the allyl trichlorosilanes and has a limited scope with
respect to the allyl donor.
aldehydes.11 In the course of our attempts to overcome this
problem, we found that whereas CuBr performed no better than
CuCl (entry 2), use of the crotyl bromide starting material led to
Received: October 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03193
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization
Table 2. Exploration of Scope for the Allyl Chloride
entry
X
CuY
additive
yield (%)
1
2
3
4
5
6
7
8
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
34
27
76
86
86
76
77
54
n-Bu4NBr
n-Bu4NI
n-Bu4NOTf
n-Bu4NBF4
n-Bu4NPF6
improved results (entry 3). While this was encouraging, the
considerable practical advantages that would accrue from the use
of allyl chlorides led us to wonder whether the bromide ion
generated in this reaction may be catalyzing the reaction, and in
turn that the reaction with crotyl chloride might be rendered
efficient by adding a bromide ion source. Indeed, it was found
that 5 mol % of n-Bu4NBr had a dramatic impact on the efficiency
of the reaction with crotyl chloride (entry 4), and we note that
the n-Bu4NBr has no impact on the Benkeser−Furuya reaction
and that there is no Finkelstein reaction under these conditions
(see Figure S2). A survey of other salts revealed that n-Bu4NI is
equally effective (entry 5), while n-Bu4NOTf, n-Bu4NBF4, and n-
Bu4NPF6 were found to be competent but less efficient catalysts
(entries 6−8).
With optimized conditions identified, we set out to explore the
scope of the reaction with respect to the allyl chloride (Table 2).
Methallyl chloride (entry 1), and functionalized methallyl
chlorides (entries 2 and 3) work well in the reaction, as do
trans-crotyl chloride (entries 4 and 5), a substituted trans-crotyl
chloride (entry 6), and trans-cinnamyl chloride (entry 7). Entry 6
is particularly noteworthy as the product of that reaction was an
intermediate in our synthesis of a “methyl-extended” linker-
equipped analogue of dictyostatin12 that was previously prepared
by an only moderately diasteroselective and inefficient process.
3,3-Disubstituted allyl chlorides also work well and allow the
establishment of all-carbon quaternary centers (entries 8 and
9).13 Halogens are well tolerated at the 2-position of the allyl
chloride leading to usefully functionalized alkene products
(entries 10 and 11),14 while heteroatom (Cl,15 BPin16)
substitution is also well tolerated at the 3-position (entries 12−
15). Control reactions with no n-Bu4NBr established that the
catalysis is in most cases critical for synthetically useful results
(entries 4a, 5, 6, 9, 12, and 13), and whereas the reactions with
simple alkyl-substituted (i.e., electron-rich) allyl donors are
efficient when run with isolated allyltrichlorosilanes (cf. Figure
1c), reactions with electronically deactivated allyl donors (entries
10−15) are not. Thus, in addition to enabling the significant
practical advance of the fully telescoped procedure that obviates
the technically difficult and tedious isolation of the allyltri-
chlorosilanes, the n-Bu4NBr catalysis also enables a substantial
expansion in scope with respect to the allyl donor.
a
The values in parentheses are the yields of the reactions with no
b
added n-Bu4NBr under otherwise identical conditions. These
reactions were conducted with benzaldehyde. This reaction was
conducted with aldehyde 4 and treated with 1 M HCl prior to workup
and product isolation to hydrolyze the ketal.
c
To demonstrate that the n-Bu4NBr catalysis can enable direct
complex fragment coupling reactions, we used diallyl chloride 5
to allylate aldehyde 6 to give 7 in 89% yield and 95% ee (Figure
2). Alcohol acetylation produced 8, which, like allyl chloride 2
comprises stereochemical complexity near the allyl chloride as
well as an acid-sensitive ketal. Initial attempts to allylate aldehyde
1 with 8 were unsuccessful due to ketal degradation presumably
Figure 2. Model fragment coupling allylation reaction for the synthesis
of the EF-half of spongistatin 1.
caused by adventitious HCl generated in the Benkeser−Furuya
reaction. While simply using excess Et3N could in principle be a
simple solution to this problem, in practice excess Et3N
B
DOI: 10.1021/acs.orglett.7b03193
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
negatively impacts the ligand complexation. Fortunately, we
found that 2,6-di-t-Bu-pyridine is an effective and otherwise
innocent base, and these modified conditions led to the isolation
of 9 in 77% yield and ≥20:1 dr. In addition to serving as a
meaningful model for the spongistatin 1 EF fragment synthesis
(cf. Figure 1a), this three-step sequence also demonstrates the
direct use of 5 as a linchpin reagent, allowing the rapid buildup of
complexity from simple starting materials.
We have measured the rate of conversion of the trans-
crotylation of benzaldehyde starting from trans-crotyltrichlor-
osilane with 5 mol % of n-Bu4NBr and with no additive (Figure
3). As chloride ion is present in these reactions and may also be
Figure 4. (a) Mechanistic scheme for Denmark’s LB-catalyzed allylation
and aldol reactions. (b) Proposed mechanism of the anion-catalyzed
allylation reaction. (c) Spectroscopic evidence for the formation of B
and G.
this mechanism highly implausible in our reactions. We propose
instead that the catalyst X‑ activates the allylsilane by forming
allylsilicate B, which binds (C) and allylates (D) the aldehyde by
way of a 6-coordinate silicate at a greatly accelerated rate (kX-)
over the coordinating anion-free background reaction (k0) before
releasing the catalyst and generating the product E (Figure 4b). A
propensity to form dianion G would be expected to inhibit the
reaction and this may provide an explanation for the poorer
performance of certain anions. Indeed, treatment of crotylsilane
10 with excess n-Bu4NBr led to 29Si NMR resonances consistent
with 5- and 6-coordinate silicates, thus providing direct
spectroscopic evidence for the formation of both B and G
(Figure 4c). Though it has been shown that strong nucleophiles
(e.g., fluoride, catecholate) may be used to preform 5-coordinate
allylsilicates that are activated for aldehyde allylsilylation
reactions,20 the effective use of more weakly coordinating anions
as catalysts reported here is without precedent. We suggest that
the key to accessing this mode of nucleophilic catalysis is the
preactivation of the silane by ligand 3, which induces Lewis
acidity7 sufficient for the reversible binding of less strongly
nucleophilic anions.
We have discovered that tetrabutylammonium salts catalyze
aldehyde allylsilylation reactions with our diaminophenol-ligated
allylsilanes. This catalysis allows both for a significant expansion
in scope with respect to the allyl donor and for the direct use of
allyl chlorides without preformation and isolation of the
allyltrichlorosilanes, which in turn allows, uniquely, for the direct
use of stereochemically and/or functionally complex allyl donors
in fragment coupling allylation reactions. The result is the most
significant progress yet reported toward the realization of a
“universal” direct aldehyde allylation reaction possessed of the
attributes outlined in Figure 1b. Mechanistically, we have secured
evidence that the catalyst plays a direct role in accelerating the
carbon−carbon bond-forming event by accessing the more
reactive 5-coordinate allylsilicate, and this may have implications
for the design of catalytic enantioselective variants of this
reaction as well as for the catalysis of a range of otherwise difficult
Figure 3. Rate measurements of the crotylation of PhCHO. Each data
point is the average of three runs (two in the case of chloride-free silane
10), measuring the disappearance of PhCHO (measuring the
appearance of product gives similar results) against a quantitative
internal standard by 1H NMR spectroscopy.
catalyzing the reaction, we also endeavored to prepare a sample
of chloride-free crotylsilane 10 in an attempt to measure the true
coordinating anion-free background reaction. Though complete
removal of the DBU·HCl salts by trituration is difficult, we were
able to isolate a sample of 10 contaminated only with ∼8% DBU·
HCl and treated it with 12 mol % of AgBArF (ArF = 3,5-
4
(CF3)2C6H3)17 prior to using it in these experiments. As shown,
the data establish that chloride and bromide greatly accelerate the
reaction relative to the coordinating anion-free background
reaction, strongly implying a direct role for the anion component
of the tetrabutylammonium salts in the catalysis.
In considering the mechanism of the catalysis, we were
cognizant of Berrisford’s report that tetra-alkylammonium salts
accelerate the DMF-promoted allylation of benzaldehyde with
allyltrichlorosilane18 and Denmark’s demonstration that n-
Bu4NI or n-Bu4NOTf led in a few cases to a modest increase
in the efficiency of Lewis base-catalyzed reactions with aliphatic
aldehydes that suffered from silylchlorohydrin formation.11,19
These effects were attributed to an increase in the ionic strength
of the medium that would be expected to favor formation of the
active ionic species 11 and to disfavor the formally neutral
silylchlorohydrin 12 (Figure 4a). The data in Figure 3 strongly
imply a direct role for the anion in our system, however, and our
allylsilane (A, Figure 4b) has no ionizable substituent, rendering
C
DOI: 10.1021/acs.orglett.7b03193
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J. Am. Chem. Soc. 2010, 132, 9153. (g) Gao, X.; Zhang, Y. J.; Krische, M.
J. Angew. Chem., Int. Ed. 2011, 50, 4173. (h) Hassan, A.; Townsend, I. A.;
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Krische, M. J. J. Am. Chem. Soc. 2011, 133, 12795.
(5) For examples of indirect fragment coupling allylation reactions
with preformation and isolation of the complex allylmetal(loid) species,
see: (a) Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765.
(b) Wender, P. A.; Hegde, S. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem.
Soc. 2002, 124, 4956.
transformations. Efforts along these lines and to further elucidate
the mechanistic details of the catalysis are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03193.
Experimental procedures and compound characterization
data (PDF)
(6) Denmark, S. E.; Weber, E. Helv. Chim. Acta 1983, 66, 1655.
(7) Suen, L. M.; Steigerwald, M. L.; Leighton, J. L. Chem. Sci. 2013, 4,
2413.
AUTHOR INFORMATION
(8) Benkeser, R. A.; Gaul, J. M.; Smith, W. E. J. Am. Chem. Soc. 1969,
91, 3666.
■
Corresponding Author
*E-mail: leighton@chem.columbia.edu.
ORCID
(9) Furuya, N.; Sukawa, T. J. Organomet. Chem. 1975, 96, C1.
(10) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620.
(11) (a) Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998,
120, 12990. (b) Denmark, S. E.; Pham, S. M.; Stavenger, R. A.; Su, X.;
Wong, K.-T.; Nishigaichi, Y. J. Org. Chem. 2006, 71, 3904. (c) Denmark,
S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405.
(d) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am.
Chem. Soc. 2005, 127, 3774.
James L. Leighton: 0000-0002-9061-8327
Author Contributions
†M.A.T.-S. and K.S.W. contributed equally.
Notes
(12) Ho, S.; Sackett, D. L.; Leighton, J. L. J. Am. Chem. Soc. 2015, 137,
14047.
The authors declare no competing financial interest.
(13) (a) Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem. 2006, 71,
1523. (b) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683.
(14) For other enantioselective aldehyde 2-haloallylation reactions,
see: (a) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111,
5495. (b) Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
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(15) For other enantioselective aldehyde α-haloallyation reactions, see:
(a) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1996, 61,
7513. (b) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Morganti, S.;
Umani-Ronchi, A. Org. Lett. 2001, 3, 1153. (c) Kobayashi, S.; Endo, T.;
Ueno, M. Angew. Chem., Int. Ed. 2011, 50, 12262.
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see: (a) Brown, H. C.; Narla, G. J. Org. Chem. 1995, 60, 4686.
(b) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
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ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award No. R01GM058133. M.A.T.-S.
is the recipient of a National Science Foundation Graduate
Research Fellowship. K.S.W. was supported by a Postdoctoral
Fellowship (124489-PF-13-311-01-CDD) from the American
Cancer Society. We thank Brian Trippe (Columbia College,
Columbia University, 2016) for developing a modification to the
synthesis of diaminophenol 3 (see the Supporting Information).
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