A continuous homologation of esters: An efficient telescoped reduction-olefination sequence

Article abstract of DOI:10.1021/ol300722e

A continuous protocol for the two-carbon homologation of esters to α,β-unsaturated esters is described. This multireactor homologation telescopes an ester reduction, phosphonate deprotonation, and Horner-Wadsworth-Emmons olefination, thus converting a three-operation procedure into a single, uninterrupted system that eliminates the need for isolation or purification of the aldehyde intermediates. The homologated products are obtained in high yield and selectivity.

Full text of DOI:10.1021/ol300722e

ORGANIC
LETTERS
2
012
Vol. 14, No. 10
465–2467
A Continuous Homologation of Esters:
An Efficient Telescoped
2
ReductionÀOlefination Sequence
Damien Webb and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, United States
tfj@mit.edu
Received March 21, 2012
ABSTRACT
A continuous protocol for the two-carbon homologation of esters to r,β-unsaturated esters is described. This multireactor homologation
telescopes an ester reduction, phosphonate deprotonation, and HornerÀWadsworthÀEmmons olefination, thus converting a three-operation
procedure into a single, uninterrupted system that eliminates the need for isolation or purification of the aldehyde intermediates. The homologated
products are obtained in high yield and selectivity.
The two-carbon homologation of esters to R,β-unsatu-
rated esters is a ubiquitous sequence in synthetic organic
chemistry. This fundamental assembly exercise can be
achieved in two synthetic steps that comprise the HornerÀ
isolation;and often purification;of aldehydes that may
be troublesome to handle.
Although one-pot procedures for this homologation
sequence have been reported, this approach has not been
widely used. Moreover, the requirement for cryogenic
temperatures renders this method undesirable for use on
5,6
a large scale. Recently, continuous flow methods have
emerged as an enabling tool, particularly for the execution
4
1
WadsworthÀEmmons olefination of an aldehyde that
is prepared by the partial reduction of an ester using
2
diisobutylaluminum hydride (DIBALH) (Figure 1a).
However, the capriciousness often observed for the
DIBALH reduction step has conferred such a notorious
reputation upon this transformation that this sequence is
3
(4) For one-pot DIBALH reduction/olefination sequences, see:
rarely used. Accordingly, one often resorts to a multistep
(
a) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986,
27, 1257–1260. (b) Hoye, T. R.; Kopel, L. C.; Ryba, T. D. Synthesis 2006,
572–1574.
5) For recent general reviews on continuous-flow chemistry, see:
a) Wirth, T. Microreactors in Organic Synthesis and Catalysis; Wiley-
VCH: Weinheim, 2008. (b) Hartman, R. L.; Jensen, K. F. Lab Chip 2009, 9,
495. (c) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.;
alternative: reduction of the ester to a primary alcohol and
then oxidation to the aldehyde, followed by the olefination
step (Figure 1b). This three-step approach is undesirable as
it generates additional waste, in addition to requiring the
1
(
(
2
McQuade, D. T. Chem. Rev. 2007, 107, 2300. (d) Geyer, K.; Gustafsson,
T.; Seeberger, P. H. Synlett 2009, 2382. (e) Kirschning, A.; Solodenko,
W.; Mennecke, K. Chem.;Eur. J. 2006, 12, 5972. (f) Wiles, C.; Watts, P.
Eur. J. Org. Chem. 2008, 10, 1655. (g) Ley, S. V.; Baxendale, I. R. Proc.
Bosen Symp., Systems Chem. 2008, 65. (h) J €a hnisch, K.; Hessel, V.;
L o€ we, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406.
(
(
1) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
2) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962,
6
19–620.
3) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854–2867.
(
1
0.1021/ol300722e r 2012 American Chemical Society
Published on Web 04/30/2012

Figure 2. General experimental setup for the continuous flow
homologation. P1, P2: precooling loops. M1, M2: T-shaped
mixers. R1, R2: reactors.
Figure 1. Strategies for the two-carbon homologation of esters
to R,β-unsaturated esters.
12
tubing and T-shaped mixers (Tefzel, 0.02 in. inner diameter).
of highly exothermic and fast chemical reactions involving
7
organometallic reagents. In this regard, we reported a
The reagent streams were introduced to the system by
syringe pump devices, and a cooling bath was used to
control the temperature (À78 or À42 °C).
simple flow system for the continuous DIBALH reduction
of esters that facilitated the rapid optimization of multiple
reaction parameters and was successfully applied to yield
a selective and reproducible synthesis of aldehydes from
In our initial study of the DIBALH reduction of esters,
we focused on developing a fast and reliable system for
aldehyde synthesis. Consequently, many of our previously
reported conditions employed an excess of DIBALH as
this enabled extremely fast conversion to the aldehyde
products. Considering the multistep homologation se-
quence holistically, we recognized that excess DIBALH
from the reduction step would negatively impact on the
HornerÀWadsworthÀEmmons olefination. As a result,
using the extensive amount of data we had collected
8
esters. In this paper, we disclose the development of a con-
9
tinuous multistep process wherein the aldehyde generated
from the DIBALH reduction is not isolated or purified
but undergoes a subsequent olefination transformation in
1
a concatenated reactor (Figure 1c). This telescoped
0
11
multistep synthesis (“one-flow” synthesis) of R,β-unsatu-
rated esters from esters affords the products in high yields
and with excellent E/Z selectivity and avoids the need to
isolate or purify the aldehyde intermediates.
Our easily configured multireactor network (Figure 2)
was assembled from standard PFA (perfluoroalkoxy alkane)
8
previously, we rapidly established a general set of flow
conditions that resulted in complete and selective reduc-
tion of the ester using only a stoichiometric quantity of
DIBALH (À42 or À78 °C with an ester flow-rate of 2.5 or
À1
5
1
mL min corresponding toa residence time(t ) of 60 or
R
3
(
6) For recent reports from our laboratory, see: (a) Bedore, M. W.;
Zaborenko, N.; Jensen, K. F.; Jamison, T. F. Org. Process Res. Dev.
010, 14, 432–440. (b) Sniady, A.; Bedore, M. W.; Jamison, T. F. Angew.
20 s, respectively). Similarly, our preliminary experiments
2
revealed that deprotonation of the phosphonate using
n-BuLi was fast (t = 8.5, or 17 s) and could be conducted
Chem., Int. Ed. 2011, 50, 2155–2158. (c) Palde, P. B.; Jamison, T. F.
Angew. Chem., Int. Ed. 2011, 50, 3525–3528. (d) Zhang, Y.; Jamison,
T. F.; Patel, S. J.; Mainofli, N. Org. Lett. 2010, 13, 280–283.
R
at room temperature. It should also be emphasized that no
precipitation was observedusingthisreagent combination.
The experimental procedure is summarized as follows
(Figure 2): A solution of DIBALH and a solution of ester
are mixed and flowed through the first reactor (R1) at low
temperature, wherein the controlled partial reduction
occurs. Solutions of the phosphonate and n-BuLi are
mixed and flowed through a second reactor (R2), wherein
the phosphonate deprotonation occurs. The outlets of
(e) Gutierrez, A. C.; Jamison, T. F. Org. Lett. 2011, 13, 6414–6417.
(7) For recent examples demonstrating the large-scale use of organo-
metallic reagents in flow, see: (a) Browne, D. L.; Baumann, M.; Harji,
B. H.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2011, 13, 3312–3315.
(
(
(
b) Fandrick, D. R. Org. Process Res. Dev. 201210.1021/op200180t.
c) Grongsaard, P. Org. Process Res. Dev. 201210.1021/op300031r.
d) Gustafsson, T.; S €o rensen, H.; Pont ꢀe n, F. Org. Process Res. Dev.
2
01210.1021/op200340c.
(8) Webb, D.; Jamison, T. F. Org. Lett. 2012, 14, 568–571.
(9) For a review, see:Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1,
6
75–680.
(
10) For the first report of a telescoped flow process that involves the
13
R1 (a solution of aluminated hemiacetal A ) and R2
preparation and use of an aldehyde of a single substrate using a
segmented flow approach, see: Carter, C. F.; Lange, H.; Sakai, D.;
Baxendale, I. R.; Ley, S. V. Chem.;Eur. J. 2011, 17, 3398–3405.
(
11) Anderson, N. G. Practical Process Research & Development;
Academic Press: San Diego, 2000; Chapter 2.
12) See the Supporting Information for full experimental details.
(13) (a) Polt, R.; Peterson, M. A.; DeYoung, L. J. Org. Chem. 1992,
57, 5469–5480. (b) Kiyooka, S.; Shirouchi, M.; Kaneko, Y. Tetrahedron
Lett. 1993, 34, 1491–1494.
(
2
466
Org. Lett., Vol. 14, No. 10, 2012

3-hydroxy-2-methylpropanoate 1e was transformed to the
homologated product 4e in high isolated yield with >95%
selectivity for the trans-alkene (Table 1, entry 5). The use of
caprolactone 1h as starting material (Table 1, entry 8)
afforded the corresponding hydroxy ester product 4h
almost quantitatively. The procedure was also successful
in providing the E-trisubstituted olefins 4i and 4j when
the phosphonopropionate 3 was employed. In all of the
examples, the amount of unwanted overreduction to the
alcohol productwasnegligibleowing tothewell-controlled
Table 1. Continuous Telescoped Homologation of Esters to
R,β-Unsaturated Esters
8
nature of the reduction step.
It is interesting to note that, in addition to an increase in
yield, the selectivity in the olefination step was consider-
ably higher than those reported previously using batch
1
4
methods with similar reagents. Also worthy of note is the
use of volatile and sensitive aldehydes, which are experi-
mentally challenging to handle when isolated prior to the
olefination step. For example, the aldehyde obtained from
the silyl ether of ethyl lactate (Table 1, entry 4) is volatile
1
5
and prone to racemization when purified. In our system,
this ester underwent partial reduction and subsequent
olefination without incident to give the desired product
4d in high yield and selectivity.
In conclusion, an efficient protocol has been developed
for the highlyselective and high-yielding continuoussynth-
esisofR,β-unsaturated estersfromesters. Themediationof
two organometallic reactions in a telescoped flow format
means the aldehyde intermediates do not have to be
isolated or purified, which greatly minimizes the amount
of waste generated for the sequence. Our future research
endeavors are focused on the evaluation and development
of other telescoped transformations.
Acknowledgment. We thank Novartis for its generous
financial support of the Novartis-MIT Center for Contin-
uous Manufacturing (CCM). Dr. Melissa Blackman
(MIT) is thanked for some preliminary experiments and
Eric Standley (MIT) for HRMS collection.
a
All yields are isolated yields (1 mmol scale) after flash chromato-
b
1
graphy with silica gel. Determined by H NMR spectroscopic analysis
of the crude product.
Supporting Information Available. Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org. The
authors declare no competing financial interest.
(
a solution of lithio-phosphonate B) are then combined in
a third mixer (which is held at low temperature). After a
steady state is reached, the final eluting stream is deposited
into a collection vessel and stirred until TLC analysis
indicates full conversion.
Using this setup, a variety of esters were investigated as
starting materials for the multistep flow process (Table 1).
In all cases, the desired products were obtained in high
yield and with high levels of selectivity for the newly
formed alkene. For example, the synthetically useful ethyl
(
14) For example, see ref 6a and:Claridge, T. D. W.; Davies, S. G.;
Lee, J. A.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Toms, S. M. Org. Lett. 2008, 10, 5437–5440.
(
15) Marshall, J. A.; Yanik, M. M.; Adams, N. A.; Ellis, K. C.;
Chobanian, H. R. Org. Synth. 2009, 11, 615–625.
The authors declare no competing financial interest.
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