A direct and sustainable synthesis of tertiary butyl esters enabled by flow microreactors

Article abstract of DOI:10.1039/c6cc04588j

Tertiary butyl esters find large applications in synthetic organic chemistry. A straightforward method for the direct introduction of the tert-butoxycarbonyl group into a variety of organic compounds has been developed using flow microreactor systems. The resultant flow process was more efficient, versatile and sustainable compared to the batch.

Full text of DOI:10.1039/c6cc04588j

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A direct and sustainable synthesis of tertiary butyl esters enabled
by flow microreactors
Leonardo Degennaro,a,* Daniela Maggiulli,a Claudia Carlucci,a Flavio Fanelli,a Giuseppe Romanazzib
and Renzo Luisia,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tertiary butyl esters find large applications in syntetic this strategy uses a peroxide and a transition metal. An
organic chemistry. A straightforward method for the direct interesting strategy, using the safer and inexpensive di-tert-
introduction of the tert-butoxycarbonyl group into a variety of butyldicarbonate (Boc)2O and aryl- and heteroarylboronates,
organic compounds has been developed using flow has been recently reported by Islam and co-workers.[9] This
microreactor systems. The flow process resulted more greener approach relies on the use of mesoporous silica grafted
efficient, versatile and sustainable compared to batch.
Pd(II) complex and works well for the preparation of aromatic
and heteroaromatic derivatives (Scheme 1, b).
The prominence of ester functionality is widely recognized in
organic chemistry. Esters are predominant among organic
compounds such as fine chemicals, materials, natural and
pharmaceutical products, and synthetic chemists have
developed several strategies for their preparation.[1] Among
the ester groups, tertiary butyl esters hold great importance
because the tert-butyl group acts as protecting group for acids,
alcohols, phenols and in peptide synthesis,[2] it is stable toward
strong organometallic bases, such as organolithiums and
organomagnesiums, and it is readily removed by acids.
However, the preparation of tertiary butyl esters is not as
straightforward as thought, and for this reason the
development of mild methodologies for their synthesis remain
a current challenge.[3] In fact, several methodologies have
recently appeared into the literature for the preparation of
tertiary butyl esters. In Scheme 1, some of these strategies
currently used for the introduction of the tert-butoxycarbonyl
(Boc) functionality into organic molecules are reported. An old
strategy relies on the use of gaseous isobutylene which poses
safety concerns for large scale applications because of the high
flammability of the gas and the explosion danger.[4] Alternative
strategies use tert-butyl methyl ether and carboxylic acids
under harsh conditions.[5] Metal-catalyzed and metal-free
carbonylation strategies, developed for the introduction of the
Boc group on the aromatic ring, have the drawback of using
toxic CO, transition metals, and seldom are conducted in not so
green solvents (Scheme 1, a).[6],[7] The use of tert-butyl
peroxide has been proposed by Wei for the conversion of
aldehydes into the corresponding tert-butyl esters.[8] However,
Scheme 1. Strategies for accessing tertiary butyl esters.
Although (Boc)2O is a well recognized electrophilic partner for
O- and N-nuclophiles, this could not be verified in the case of
strong C-nucleophiles such as organolithiums
or
organomagnesiums, and we were able to find only few isolated
examples into the literature.[10] One reasonable reason for the
missing use of (Boc)2O with carbanions could be the predictable
side reaction of multiple addiction. Thus, we reasoned that
coupling of (Boc)2O with nucleophilic organometallics could be
a direct and straightforward strategy, for preparing a plethora
of tert-butyl esters, complementing those reported in Scheme
1. With the aim to develop a direct and more sustainable
approach to tert-butyl esters we investigated this strategy using
flow microreactor systems and the results of this study are
reported herein. The use of flow microreactors as sustainable
technology for performing chemical synthesis is now growing in
importance and is being appreciated in both academia and
industry. [11]
a. Department of Pharmacy ꢀ Drug Sciences, University of Bari ꢁA. Moroꢂ, FLAME ꢀ
Lab Flow Chemistry and Microreactor Technology Laboratory, Via E. Orabona 4,
Bari 70125 ꢀ Italy.
b. DICATECh, Politecnico di Bari, Via E. Orabona 4, Bari 70125 ꢀ Italy.
Footnotes relang to the tle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
The precise thermal profile realized in a microreactor, allows to
avoid or limit side products especially for rapid and very
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exothermic reactions.[12] This is especially true in the case of Table 1. Optimization of the reaction of organolithiums with
organolithiums which react rapidly with electrophiles giving (Boc)2O in flow conditions.
often highly exothermic reactions, under traditional batch
conditions, thus requiring cryogenic conditions. However,
Yoshida widely demonstrated that flow microreactor systems
could be used to handle organolithiums bearing sensitive
functional groups, by controlling the residence time and the
temperature. In fact, this technology enabled the direct
introduction of substituents on the aromatic ring, without
(Boc)2O
Ester[b] Alcohol[b]
Entry
Flow [a]
tR1 (s)
23.56
11.78
6.04
R-Li (eq)
HexLi (1)
HexLi (1)
HexLi (1)
HexLi
protecting the nitro-, cyano-, keto- and alkoxycarbonyl-groups,
definitively susceptible to attack by the organolithium itself.[13]
In continuation of a research programme focused on the use of
microreactor technology in the development of sustainable
synthetic processes[14], we became involved in the preparation
of tertiary butyl esters by addition of organolithiums to (Boc)2O.
The investigation started using hexyllithium as suitable
nucleophile, (Boc)2O as electrophile and 2-MeTHF as a greener
solvent.[15], [14b] The reaction was first conducted in batch
conditions (Scheme 2); to a solution of Boc2O in 2-MeTHF, an
equimolar amount of HexLi was added at two different
temperatures, -78 °C and 25 °C obtaining in each case a different
1
2
3
A
B
C
1
1
44
50
75
56
50
25
0.95
4
5
D
D
5.61
5.61
1
1
96
95
4
5
PhLi (1.1)
[a] Flow rate: A: RLi = 0.5 mL/min, Boc2O = 0.5 mL/min; B: RLi = 1
mL/min, Boc2O = 1 mL/min; C: RLi = 2 mL/min, Boc2O = 1.9
mL/min; D: RLi = 2.2 mL/min, Boc2O = 2 mL/min. [b] Calculated by
gas chromatoghraphy.
Next, the temperature effect on the progress of the reaction
was evaluated using HexLi and (Boc)2O (Table 2). Three different
conditions were considered, increasing the temperature of
about 25 °C for each run. With our delight, we found that the
process can be conducted efficiently even at 25 °C maintaining
mixture of adducts
temperature (i.e. -78 °C) considerable amounts of tertiary
alcohol formed, and it becomes the main product running the
reaction at 25 °C. However, such side reaction is likely
responsible for the low conversions (up to 44%) observed.
1 and 2. As expected, even at low
2
the amount of the alcohol
2 at acceptable level.
Batch mode
O
OH
Table 2. Effect of the temperature.[a]
HexLi
+
(Boc)2O
OtBu
+
2-MeTHF
T °C
[c]
[c]
1
2
HexLi (eq)
1.1
tR1 (s) [b]
5.61
Boc2O (eq)
T (°C)
-30
0
1
%
2
%
7
T = -78 °C
T = 25 °C
1
1
1
93
95
93
15%
7%
25%
37%
1.1
5.61
5
Scheme 2. Addition of organolithiums to (Boc)2O.
1.1
5.61
25
7
[a] The microflow system reported in Table 1 was employed. [b] Flow
rate: HexLi = 2.2 mL/min, Boc2O = 2 mL/min. [c] Calculated by gas
Thus, we transferred the reaction in a flow microreactor system
consisting in a T-shaped stainless steel micromixer (M1), two chromatoghraphy.
pre-cooling units (P1, P2) and a microtube reactors (R1) (Table
Further, we decided to explore the scope of this process using
1). Optimization experiments were carried out feeding the flow
system with a solution of (Boc)2O (0.1 M in 2-MeTHF), and a
solution of hexyllithium (0.1 M in hexane) at -50 °C, and
quenching the reaction at the output with an aqueous solution
of NH4Cl (Table 1). The reactants were introduced into the flow
other organolithiums, easily generated by halogen/lithium
exchange reaction or by deprotonation. With the aim to
develop a more sustainable process, hexyllithium, which is
more stable and less pyrophoric compared to MeLi, t-BuLi, i-PrLi
and n-BuLi, was chosen as the lithiating agent for the halogen
exchange reactions on readily available aryl- and heteroaryl
bromides.[15] The greener 2-MeTHF was employed as the
solvent. First, the Br/Li exchange reaction was optimized using
1-bromo-4-chlorobenzene 5a as reference substrate, and using
a flow microreactor system consisting of three precooling units
(P1, P2 and P3), two residence units (R1 and R2), and two T-
shaped micromixer (M1 and M2) (Table 3). In order to set up
the microflow system, conditions reported by Yoshida and co-
workers were used as reference for the halogen/lithium
exchange reaction and for setting R1 and tR1.[16] In our system
(Table 3) a residence time tR1 of 0.7 s was found as optimum for
a complete Br/Li exchange. However, the reaction of the
aryllithium with (Boc)2O needed further optimization as
reported in Table 3. In order to get high conversion, the
residence time in R2 (tR2) was optimized using conditions
reported in Table 3. Tert-butyl ester 6a was obtained in 90%
yield with 17.1 s as tR2 (Table 3, entry 4). It is worth mentioning
system by using syringe pumps. The residence times in R1 (tR1
)
were determined by choosing properly the flow rates while
maintaining an almost equimolar stoichiometry for HexLi and
(Boc)2O (Table 1). The optimization study demonstrated that
the residence time is a critical parameter. In fact, longer
residence times (Table 1, entries 1-3) favor the multiple addition
of the organolithium. Reducing the residence to 5.6 seconds,
gave the best results in terms of selectivity furnishing 96% of
the desired ester
1 (Table 1, entry 4). We considered that,
higher flow rates could guarantee a better mixing efficiency in a
multilamination-type micromixer, by virtue of the short
diffusion path, along with a shorter residence time thus
avoiding multiple addition products. Under such optimized
conditions, the use of PhLi resulted in 95% yield of tert-butyl
benzoate 3 (Table 1, entry 5).
It is worth pointing out that this reaction performed in batch at
-78 °C, under the same conditions reported in Scheme 2,
furnished almost exclusively alcohol 4.
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that the lithiation/esterification sequence was performed at 0 and are difficult to obtain straightforwardly under batch
°C and not under cryogenic conditions (i.e. -78 °C). conditions. In fact, running this reaction in batch mode even at
Table 3. Optimization study of the lithiation/trapping sequence. -78 °C returned only complex mixtures with trace of 8.
[a]
Entry
Flow
R2 (cm)
145
tR2 (s)
7.35
(Boc2)O [b]
58%
6a yield[c]
42%
1
2
3
4
A
B
C
D
145
9.11
55%
45%
145
11.38
17.1
40%
60%
200
10%
90%
[a] Flow rate: A: ArBr 2 ml/min, HexLi 2 ml/min, Boc2O 5,3 ml/min; B:
ArBr 2 ml/min, HexLi 2 ml/min, Boc2O 3,5 ml/min; C: ArBr 2 ml/min,
HexLi 2 ml/min, Boc2O 2 ml/min; D: ArBr 2 ml/min, HexLi 2 ml/min,
Boc2O 1,5 ml/min. [b] Remaining (Boc)2O. [c] Calculated by 1H NMR of
the crude reaction mixture.
Under optimized conditions, tert-butyl ester 6a could be
obtained with a productivity of 1.3 g/h just feeding the
microreactor system for 30 minutes with the reactantsꢀ
solutions. Once optimized the reaction under flow conditions
for 1-bromo-4-chlorobenzene, we explored the scope of this
direct lithiation/tert-butoxycarbonylation (Scheme
3 and
supplementary material). We were pleased to find that this
protocol worked well for several aryl and heteroaryl bromides
5b-j, and could be conducted at higher temperature with
respect to batch mode. In the case of fluorinated derivative 5c
,
the use of tmeda was mandatory in order to prevent
precipitation of the lithiated intermediate, and clogging of the
flow system. Heteroaryl bromides 5h-j were effectively
functionalized without observing any side reaction. In the case
of 5h, the reaction needed a lower temperature (-40 °C) to
succeed. Under optimized conditions, the lithiation/ter-
butoxycarbonylation of different acetylene derivatives was
pursued. This reaction is particularly useful because tert-butyl
propiolates are difficult to obtain, and are useful starting
material in [4 +2] cycloaddition reactions.[17] The microfluidic
system reported in Scheme 3 allowed to prepare aryl and
heteroaryl tert-butyl propiolates 6k-p with good to excellent
yields at temperatures in the range between 20 and 0 °C
(Scheme 3). The direct introduction of the tertiary ester was
Scheme 3. Scope for the direct ter-butoxycarbonylation in flow.
Aware of the importance of tert-butyl esters, we attempted the
direct tert-butylcarbonylation on the aromatic ring of 9 where
another ethyl ester was already installed (Scheme 4, b). Starting
from Yoshida conditions,[13c] using the microfluidic system
reported in Scheme 4 working at -40 °C with tR1 0.3 s, we were
able to generate the organolithium 9-Li in R1, after mixing
with PhLi. Transferring 9-Li in M2 allowed its reaction with
Boc2)O that was completed in R2 in 5.4 s leading to the bis-
9
extended to b-bromo styrene 5q obtaining the corresponding
ester 6q in almost quantitative yield. However, in this case sec-
BuLi was used as lithiating agent at a temperature of -20 °C.[18]
As further application of this strategy for the direct preparation
of tertiary butyl esters, we investigated two challenging
substrates where regioselectivity problems can be envisaged.
As reported in Scheme 4, 4-bromoisoquinoline 7 if reacted with
an alkyllithium could undergo either bromine/lithium exchange
reaction or nucleophilic attack at the C1. Under optimized
(
ester 10 in 65% yield. This result is, in our opinion, remarkable
because it shows how microreactor systems can make
practicable reactions that are difficult to perform in batch
conditions.
conditions (tR1 0.7 s, tR2 17.1 s, T = 0 °C) using 1 equiv of
7 and
1.1 equiv of HexLi (see supplementary material) a regioselective
nucleophilic addition at the C1 occurred leading to 7-Li that
reacted at the nitrogen with (Boc)2O in M2 giving 82% yield of
adduct 8. It is worth pointing out that this kind of bromo
derivatives could serve as synthons for other transformations,
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challenging systems.
In conclusion, in this work we have demonstrated that precise
control of residence time and temperature, realized in a flow
microreactor system, allow to perform
a direct and
13. a) H. Kim, A. Nagaki, J.-i. Yoshida, Nat. Commun. 2011,
2
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organolithiums in 2-MeTHF as the solvent. It is worth
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We thank the University of Bari ꢁA. Moroꢂ, Regional Project
ꢁFuture in Researchꢂ (project code TBFPTF6); Regional project
ꢃꢃReti di Laboratori Pubblici di Ricercaꢀꢀ (Projects: Code 20 and
68). Laboratorio SISTEMA, (Code PONa300369) financed by
Italian Miur. We thank Marco Colella and Manuela Delfine for
contributing to set up experiments.
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