Automated synthesis: Utilization of MEDLEY in synthetic processes

Article abstract of DOI:10.1021/op0000475

A variety of reactions which are commonly used in synthetic chemistry are feasible with the automated synthesizer (MEDLEY). Air-sensitive organolithium and Grignard reagents as well as transition metal catalysts like Ni(0) and Pd(0) species are employable. The precise control of both the reaction temperature and the amount of added reagents enables to examine the dependence of chemical yields on the reaction temperature. Since the order of reagent addition is programmed and the reaction temperature is quickly tunable, sequential reactions can be conducted smoothly. An advanced control system was incorporated which allows a task to start immediately after the preceding one has finished. Owing to this function, the time for completing the multistep process can be minimized.

Full text of DOI:10.1021/op0000475

Organic Process Research & Development 2000, 4, 337−341
Automated Synthesis: Utilization of MEDLEY in Synthetic Processes
Akihiro Orita, Yutaka Yasui, and Junzo Otera*
Department of Applied Chemistry, Okayama UniVersity of Science, Ridai-cho, Okayama 700-0005, Japan
Scheme 1a
Abstract:
A variety of reactions which are commonly used in synthetic
chemistry are feasible with the automated synthesizer (MED-
LEY). Air-sensitive organolithium and Grignard reagents as
well as transition metal catalysts like Ni(0) and Pd(0) species
are employable. The precise control of both the reaction
temperature and the amount of added reagents enables to
examine the dependence of chemical yields on the reaction
temperature. Since the order of reagent addition is programmed
and the reaction temperature is quickly tunable, sequential
a Yield obtained by manual operation.
reactions can be conducted smoothly. An advanced control
system was incorporated which allows a task to start im-
mediately after the preceding one has finished. Owing to this
function, the time for completing the multistep process can be
minimized.
Scheme 2a
Introduction
In the preceding contribution, we reported a new type of
automated synthesizer (MEDLEY) which allows reactions
under the same reaction conditions as those which synthetic
chemists employ in normal bench work.1 One of the purposes
of this work is to demonstrate that the synthesizer is actually
applicable to various synthetic reactions, in particular, under
an inert atmosphere.
MEDLEY can control the amounts of reagents to be added
within a (0.01 mL deviation. The reaction temperature can
also be regulated from -80 to 30 °C, accurate within (0.1
°C. Such precise control of the reaction conditions allows
us to examine the influences of reaction conditions on the
carbanion reactions which are heavily affected by reaction
parameters. Thus, the next purpose of this work is to show
that such influences can be well assessed by the use of
MEDLEY.
Of more practical importance is the feasibility of multistep
processes to run on MEDLEY. The chemical processes are
usually composed of a number of operations. The first
reaction transforms a starting material to an intermediate
which, after isolation and purification, is subjected to the
second reaction leading to the next intermediate. Repetition
of these operations drives the process to the final product.
The automation of such multistep processes is of great
importance from both economical and ecological points of
view. We previously advanced a new concept for one-pot
reaction, “integrated chemical process”, which enables
integration of ordinary reactions under ordinary conditions.2
It would be of great promise if integrated chemical processes
could be operated automatically. Hence, the third purpose
a Yield obtained by manual operation.
of this work is to demonstrate the successful accommodation
of sequential reactions in MEDLEY.
Finally, another characteristics of MEDLEY will be
disclosed, the advanced control which allows the next task
to start immediately after the previous one has finished. Due
to the absence of a dead time between contiguous tasks, the
processing time could be minimized. This will be proved to
be indeed the case.
Results and Discussion
First, employment of air-sensitive organolithium and
Grignard reagents were checked. The reaction proceeded
smoothly to afford the yields comparable to those obtained
by manual operations (Scheme 1).
Then, the utility is further exemplified by the successful
use of air-sensitive transition metal catalysts. The Ni(0)
catalyst was generated in situ without problem and the two
types of coupling reactions proceeded smoothly (Schemes
23 and 34). The feasibility of Pd(0)-catalyzed reaction was
proved with Suzuki-Miyaura coupling (Scheme 4).4 As a
(2) (a) Orita, A.; Yamashita, Y.; Toh, A.; Otera, J. Angew. Chem., Int. Ed.
Engl. 1997, 36, 779. (b) Orita, A.; Yoshioka, N.; Otera, J. Chem. Lett. 1997,
1023. (c) Orita, A.; Watanabe, A.; Otera, J. Chem. Lett. 1997, 1025. (d)
Orita, A.; Watanabe, A.; Tsuchiya, H.; Otera, J. Tetrahedron 1999, 55, 2889.
(e) Orita, A.; Yoshioka, N.; Struwe, P.; Braier, A.; Beckmann, A.; Otera, J.
Chem. Eur. J. 1999, 5, 1355. (f) Orita, A.; Yaruva, J.; Otera, J. Angew.
Chem. 1999, 111, 2397; Angew. Chem., Int. Ed. 1999, 38, 2267.
(3) Dubois, F.; Gingras, M. Tetrahedron Lett. 1998, 39, 5039.
(1) Orita, A.; Yasui, Y.; Otera, J. Org. Process Res. Dev. 2000, 4, 333.
(4) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37, 2993.
10.1021/op0000475 CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 08/10/2000
Vol. 4, No. 5, 2000 / Organic Process Research & Development
•
337

Scheme 3a
Table 2. Effect of rate of aldehyde addition on yields in
Aldol reactiona
time consumed
for adding 15,
min
temperature during
BuLi addition,
°C
yield of 16,
entry
%
1
2
3
4
5
20
10
5
3
1
-74.0 to -72.6
-74.0 to -72.4
-74.0 to -69.9
-74.0 to -67.3
-74.0 to -63.5
95
95
96
92
83
a Yield reported.
Scheme 4a
a Reaction conditions: 14 (10 mmol), BuLi (11 mmol, 8.46 mL); 15 (12
mmol), THF (20 mL).
with increase in the rate of BuLi addition. This is attributed
to the competing cleavage of the trimethylsilyl group to
generate the sulfonyl anion 13 (eq 1). The highest temper-
a Yield reported.
Table 1. Effect of rate of BuLi addition on yields in
Peterson eliminationa
atures reached during the addition are also shown in Table
1 and are totally parallel with the addition rates. The reaction
temperature was raised above -70 °C even by very slow
addition (9.25 mL/20 min). At the addition rates that we
employ in normal synthetic operations (9.25 mL/5-10 min),
the reaction temperature jumped to ∼-60 °C. These results
reveal that the reaction temperature fluctuates more vigor-
ously than we imagine and should be controlled carefully if
strict control of the temperature is required.5 Next the effect
of aldehyde addition was examined for simple aldol-type
reactions (Table 2). The lithiation of 14 was conducted below
-70 °C, and the time for adding aldehyde 15 was changed
from 20 to 1 min. The similar variation of the yield was
observed although the degree of fluctuation was not so large
as that for the former case. The decrease of the yield of 16
at higher temperature may come from the side reactions such
as deprotonation of aldehyde 15, etc.
With these results of elementary reactions in hand, we
turned our attention to sequential reactions. The double
alkylation of an allylic sulfone was our first choice (Scheme
5).2c,d Prenyl sulfone 17 was lithiated, and the resulting anion
was treated with decyl bromide. To this reaction mixture
was added BuLi followed by cinnamyl bromide. The usual
aqueous workup provided the double alkylation product 18
in 82% yield by manual operations. The same reaction was
conducted on MEDLEY which executed 14 programmed
operations. The reactor was purged with nitrogen, and then
the automation process was triggered. After this stage, no
further manual operations were needed until the completion
time consumed
for adding BuLi,
min
temperature during
BuLi addition,
°C
yield of 12,
entry
/%
1
2
3
4
5
20
10
5
3
1
-74.0 to -69.4
-74.0 to -62.4
-74.0 to -61.1
-74.0 to -56.3
-74.0 to -44.1
97
88
87
84
71
a Reaction conditions: 10 (10 mmol), BuLi (12 mmol, 9.25 mL); 11 (12
mmol), THF (20 mL).
result, it is concluded that most of synthetic reactions
employing air-sensitive compounds can be performed suc-
cessfully on MEDLEY.
It is well-known that reactions of carbanions are highly
dependent on the reaction temperature. Thus, synthetic
chemists are forced to regulate the rate of reagent addition
to maintain the reaction at a required temperature. However,
this is usually done empirically without information about
what is actually happening in the flask. Since the real reaction
temperature can be measured precisely on MEDLEY, varia-
tions in the reaction temperature depending on the addition
rate were probed for aldol-type reactions. First, generation
of the lithium anion from R-silyl benzyl sulfone 10 was
examined (Table 1).2e The time for adding BuLi was altered
from 20 to 1 min. The resulting anion was trapped with
anisaldehyde 11 to give vinyl sulfone 12 via Peterson
elimination. The yield of 12 was straightforwardly decreased
(5) In usual experiments, the temperature of the cooling bath, not the reaction
medium itself, is measured. When the same reaction was carried out by
using a normal cooling bath, without the use of the reactor for MEDLEY,
the temperature of the reaction solution rose similarly.
338
•
Vol. 4, No. 5, 2000 / Organic Process Research & Development

Scheme 5
Scheme 6
of the process. The yield of 18 was comparable to that
obtained by the manual operations.
Then, we ran the integrated chemical process of the double
elimination protocol for the one-pot synthesis of acetylenes
(Scheme 6).2e Sixteen operations were programmed for this
process. After the reaction flask was filled with a THF
solution of sulfone under a nitrogen atmosphere, the program
was initiated, and all operations proceeded automatically.
First, the reactor was cooled by circulating cold MeOH (-85
°C). The solution became -74 °C after 5 min (operation 1).
The additions of BuLi, TMSCl, aldehyde 20, and a base were
conducted according to the progamme to keep the reaction
temperature below -70 °C (operations 2, 4, 8, 10, and 14).
All of these operations were completed actually within 5 min.
The temperature fluctuated between -74 and 70 °C. As soon
as these tasks finished, the next operations started im-
mediately as a result of the advanced control function. After
operations 4 and 10, the flow of cold MeOH stopped, and
warm MeOH (room temperature) started to circulate. The
reaction temperature reached 15 or 0 °C, respectively, within
5 min. On the other hand, in operations 7 and 13, the
temperature was cooled to -74 °C within 10 min as
described for operation 1. Thus, the ups and downs of the
reaction temperature that are frequently encountered in anion
chemistry are readily achievable. In the event, 16 operations
were done without any manual work. Upon the finish of the
programmed tasks, the reaction mixture was subjected to
usual aqueous workup to give satisfactory yields of the
desired acetylenes 21. It is apparent from the above results
that the computer program effectively enables the mainte-
nance, warming, and cooling of the reaction temperature as
well as the addition of the reagents in the required order
and amount.
side reactions or decompositions of the products that may
arise upon unnecessarily long reaction can be avoided.6 The
advantage of this system was assessed for the Peterson
elimination reaction in detail (Table 3). The reaction tem-
perature was programmed to be kept below -70 °C during
the anion generation, and the time required for completing
addition of BuLi was measured. In six runs, the times
fluctuated extensively from 18′ 31′′ to 23′ 58′′ despite the
relatively small reaction scale. Such big fluctuations are
rather surprising, considering the precise control of the
reaction temperature as well as the amount of the BuLi
added. In the time-controlled system, the programming of
at least 25 min would be required to secure the completion
of the task. Thus, the considerably long dead time (possibly
6′ 30′′ at most) is inevitable, and the accumulation of such
intervals in the sequential process should result in wasting a
lot of processing time. Of course, the time loss would be
greater for reactions in larger scale.
In conclusion, an automated synthesizer has been devel-
oped which enables to conduct manifold reactions sequen-
tially under the conditions that are employed in usual
synthetic reactions. Through the advanced control, the time
required for connecting the successive operations are mini-
mized. “Integrated chemical process” has proved to be, in
As revealed above, the advanced control system is of great
use for minimizing the process time. Moreover, undesired
(6) For “overnight stirring problem”, see ref 5 of ref 1 of this paper.
Vol. 4, No. 5, 2000 / Organic Process Research & Development
•
339

Table 3. Variation of the time required for addition of BuLi
column chromatography on silica gel (hexane/EtOAc, 9:1)
to give pure butyl phenyl ketone (256 mg, 79% yield).
Reaction of Ethyl Magnesium Bromide and Benzal-
dehyde. A flask was evacuated and filled with nitrogen. After
THF (6 mL) and benzaldehyde (212 mg, 2.0 mmol) were
added, the mixture was kept at 30 °C in the water bath. Then,
the program was initiated. When the temperature of the
reaction mixture reached 30 °C, the addition of a THF
solution of EtMgBr started. The reaction temperature was
kept at 30 °C. After completion of the EtMgBr addition (1.0
M, 2.4 mL, 2.4 mmol), the mixture was further stirred at 30
°C for 24 h, and water (30 mL) was added. After usual
aqueous workup, the crude products were subjected to
column chromatography on silica gel (hexane/EtOAc, 4:1)
to give pure 1-phenylpropanol (199 mg, 73% yield).
Nickel-Catalyzed Methylation of Binaphthyl Triflate
(5). A flask was evacuated and filled with nitrogen. After
addition of ether (8 mL), binaphthyl triflate (5) (1101 mg, 2
mmol), and NiCl2(dppp) (54 mg, 0.1 mmol), the program
was initiated. When the temperature of the ether solution
reached 0 °C by circulating cold methanol, the addition of
an ether solution of MeMgBr started. The reaction temper-
ature was kept at 0 °C. After completion of MeMgBr addition
(3.0 M, 2.67 mL, 8.0 mmol), the mixture was stirred at 0
°C for 1 h. The reaction mixture was warmed to 25 °C and
stirred at this temperature for 3 h. After addition of water
(30 mL) followed by usual aqueous workup, the crude
products were subjected to column chromatography on silica
gel (hexane/EtOAc, 95:5) to give the pure product (525 mg,
93% yield).
Nickel-Catalyzed Suzuki-Miyaura Coupling Reaction.
A flask was evacuated and filled with nitrogen. After
additions of 1,4-dioxane (7 mL), K3PO4 (1273 mg, 6.0
mmol), and NiCl2(dppp) (54 mg, 0.1 mmol), the program
was initiated. A hexane solution of BuLi (1.6 M, 0.5 mL,
0.8 mmol) was added at 25 °C, and the mixture was stirred
at 25 °C for 10 min. A dioxane solution of 3-chlorotoluene
(253 mg, 2.0 mmol) and dihydroxy phenylborane (268 mg,
2.2 mmol) was added, and the mixture was heated at 80 °C
for 24 h. After addition of water (30 mL) followed by usual
aqueous workup, the crude products were subjected to
column chromatography on silica gel (hexane/EtOAc 98:2)
to give the pure product (289 mg, 86% yield).
in Peterson eliminationa
temperature during
time consumed
for adding BuLi
BuLi addition,
yield
of 12/%
entry
°C
1
2
3
4
5
6
18′ 58′′
22′ 47′′
20′ 33′′
23′ 58′′
20′ 20′′
18′ 31′′
-73.6 to -69.8
-73.5 to -69.9
-73.5 to -69.6
-73.6 to -70.0
-73.5 to -69.8
-73.6 to -69.6
96
97
98
96
96
98
a Reaction conditions: 10 (10 mmol), BuLi (12 mmol, 9.25 mL); 11 (12
mmol), THF (20 mL).
fact, a useful concept for automation of multistep chemical
processes. Of course, it is not always possible to consolidate
all reactions needed in a whole synthetic route. Nevertheless,
it is highly useful even if only a part of the synthetic sequence
is consolidated. As such, we are now in a position to run
consecutive reactions with the automated synthesizer without
difficulty.
Experimental Section
General. All of the reactions were carried out under
nitrogen. Tetrahydrofuran (THF) and diethyl ether were
distilled from sodium benzophenone ketyl. Dioxane and
dimethoxyethane (DME) were distilled from calcium hydride.
NMR spectra were recorded at 25 °C on JEOL Lambda 300
and JEOL Lambda 500 spectrometers and calibrated with
tetramethylsilane (TMS) as an internal reference. Silica gel
(Daiso gel IR-60) was used for column chromatography.
Sulfones were prepared according to the procedures described
in the literature.7,8 The following compounds are known, and
the spectral data of these compounds were consistent with
those in the literature: 2,9 4,10 6,3 9,4 and 4-methoxy-1-[2-
(4-methoxyphenyl)ethynyl]benzene.11
Reaction of Butyl Lithium and Methyl Benzoate. A
reaction flask was evacuated and filled with nitrogen. After
THF (6 mL) and methyl benzoate (272 mg, 2.0 mmol) were
added, the mixture was cooled in a dry ice/methanol bath.
Then, the program was initiated. When the temperature of
the reaction mixture reached -78 °C, the addition of a
hexane solution of BuLi started. The bath temperature was
kept at -78 °C. After completion of BuLi addition (1.52
M, 2.63 mL, 4.0 mmol), the flask was placed in an ice/water
bath, and the mixture was stirred for 24 h. After usual
aqueous workup, the crude products were subjected to
Palladium-Catalyzed Suzuki-Miyaura Coupling Re-
action. A flask was evacuated and filled with nitrogen. After
addition of DME (5 mL), water (1 mL), Na2CO3 (318 mg,
3.0 mmol), and Pd(PPh3)4 (34 mg, 0.03 mmol), the program
was initiated. A DME solution (1 mL) of 3-chlorobenzonitrile
(138 mg, 1.0 mmol) and dihydroxy phenylborane (134 mg,
1.1 mmol) was added at 25 °C, and the mixture was heated
at 80 °C for 24 h. After addition of water (30 mL) followed
by usual aqueous workup, the crude products were subjected
to a column chromatography on silica gel (hexane/EtOAc,
95:5) to give the pure product (141 mg, 79% yield).
Peterson Olefination between Silyl Sulfone 10 and
Aldehyde 11. The reactor having a jacket for circulation of
methanol was evacuated and filled with nitrogen. After THF
(20 mL) and silyl sulfone 10 (3.34 g, 10 mmol) were added,
(7) LeBel, N. A.; Balasubramanian N. J. Am. Chem. Soc. 1989, 111, 3363.
(8) Kondo K.; Tunemoto, D. Tetrahedron Lett. 1975, 1007.
(9) Alonso, F.; Lorenzo, E.; Yus, M. J. Org. Chem. 1996, 61, 6058.
(10) Kuwano, R.; Uemura, T.; Saitoh, M.; Ito, Y. Tetrahedron Lett. 1999, 40,
1327.
(11) Mouries, V.; Waschbuesch, R.; Carran, J.; Savignac, P. Synthesis 1998,
271.
340
•
Vol. 4, No. 5, 2000 / Organic Process Research & Development

the program was initiated. In this case, the advanced control
was not invoked, and the rate of BuLi addition was time-
controlled. After the temperature of the reaction mixture
reached -74 °C, a hexane solution of BuLi (1.3 M, 9.25
mL, 12 mmol) was added over the period required. After
the completion of the BuLi addition, the reaction mixture
was stirred at the same temperature for 30 min. Then,
p-anisaldehyde (1.46 mL, 12 mmol) was added. The mixture
was warmed to 0 °C and stirred for 2 h. After addition of
saturated NH4Cl solution (30 mL) followed by usual workup,
mixture was cooled to -74 °C again, and a hexane solution
of BuLi (1.52 M, 1.38 mL, 2.1 mmol) was added. After 30
min, cinnamyl bromide (0.31 mL, 2.1 mmol) was added,
and the mixture was stirred at 15 °C for 18 h. After addition
of saturated NH4Cl solution (30 mL) followed by usual
aqueous workup, the crude products were subjected to
column chromatography on silica gel (hexane/EtOAc, 80:
20) to give the pure product (570 mg, 80% yield); 1H NMR
(CDCl3) δ 0.87 (t, J ) 6.8 Hz, 3H), 1.1-1.3 (m, 16H), 1.47
(s, 3H), 1.75 (s, 3H), 1.90-2.00 (m, 1H), 2.03-2.10 (m,
1H), 2.73-2.80 (m, 1H), 2.99-3.06 (m, 1H), 4.86 (s, 1H),
6.2-6.4 (m, 1H), 6.46 (d, J ) 15.7 Hz, 1H), 7.18-7.36 (m,
5H), 7.49-7.57 (m, 2H), 7.59-7.66 (m, 1H), 7.80-7.88 (m,
2H).
Synthesis of Diarylacetylenes (21) (Representative).
The reactor having a jacket for circulation of methanol was
evacuated and filled with nitrogen. THF (6 mL) and
p-methoxybenzyl sulfone (524 mg, 2.0 mmol) were added,
and then the program was initiated. The mixture was cooled
to -74 °C, and a hexane solution of BuLi (1.52 M, 1.45
mL, 2.2 mmol) was added. The mixture was stirred for 30
min. After addition of Me3SiCl (0.28 mL, 2.2 mmol), the
mixture was warmed to 15 °C and stirred for 1 h. The
mixture was cooled to -74 °C again, and a hexane solution
of BuLi (1.52 M, 1.58 mL, 2.4 mmol) was added. After 30
min, p-anisaldehyde (0.29 mL, 2.4 mmol) was added. The
mixture was warmed to 0 °C and stirred at this temperature
for 2 h. The mixture was cooled to -78 °C, and LDA was
added. The mixture was stirred at -78 °C for 2 h, and
saturated NH4Cl solution (30 mL) was added. After usual
workup, the crude products were subjected to column
chromatography on silica gel (hexane/EtOAc, 70:30) to give
the pure product (396 mg, 83% yield).
1
the yield was determined on the basis of HPLC; H NMR
(CDCl3) δ 3.75 (s, 3H), 3.82 (s, 3H), 6.70 (d, J ) 8.9 Hz,
2H), 6.82 (d, J ) 8.9 Hz, 2H), 6.94 (d, J ) 8.9 Hz, 2H),
7.05 (d, J ) 8.9 Hz, 2H), 7.37-7.42 (m, 2H), 7.49-7.55
(m, 1H), 7.60-7.65 (m, 2H), 7.89 (s, 1H).
Aldol-type Reaction between Benzyl Sulfone 14 and
Aldehyde 15. The reactor having a jacket for circulation of
methanol was evacuated and filled with nitrogen. After THF
(20 mL) and benzyl sulfone 14 (2.32 g, 10 mmol) were
added, the program was initiated. The reaction mixture was
cooled to -74 °C, and a hexane solution of BuLi (1.3 M,
8.46 mL, 11 mmol) was added at this temperature. After
the completion of the addition, the mixture was stirred at
-74 °C for 30 min. Then, 15 (1.60 mL, 12 mmol) was added
over the period of 20 min at this temperature. The mixture
was stirred for 1.5 h, and saturated NH4Cl solution (30 mL)
was added. After usual workup, the yield was determined
1
on the basis of HPLC; H NMR (CDCl3) δ 1.52-1.60 (m,
1H), 1.62-1.72 (m, 1H), 2.60-2.70 (m, 1H), 2.76-2.83 (m,
1H), 3.25-3.29 (m, 1H), 3.92-4.00 (m, 1H), 4.79-4.84 (m,
1H), 7.08-7.11 (m, 2H), 7.12-7.39 (m, 10H), 7.50-7.60
(m, 3H).
Double Alkylation Reaction of Sulfone (17). The reactor
having a jacket for circulation of methanol was evacuated
and filled with nitrogen. Then, the program was initiated.
After addition of THF solution (6 mL) of prenyl phenyl
sulfone (420 mg, 2.0 mmol) at ambient temperature, the
mixture was cooled to -74 °C. A hexane solution of BuLi
(1.52 M, 1.38 mL, 2.1 mmol) was added at -74 °C, and the
mixture was stirred for 30 min. After addition of bromode-
cane (0.44 mL, 2.1 mmol), the reaction mixture was warmed
to 15 °C, and the mixture was stirred at 15 °C for 2 h. The
Acknowledgment
This work was supported by the Japan Society for the
Promotion of Science under the “Research for the Future”
Program (JSPS-PFTF96P00303).
Received for review May 2, 2000.
OP0000475
Vol. 4, No. 5, 2000 / Organic Process Research & Development
•
341