Selective Acylation of Aryl- A nd Heteroarylmagnesium Reagents with Esters in Continuous Flow

Article abstract of DOI:10.1021/acs.orglett.9b04254

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.

Full text of DOI:10.1021/acs.orglett.9b04254

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Acylation of Aryl- and Heteroarylmagnesium Reagents
with Esters in Continuous Flow
Benjamin Heinz,‡ Dimitrije Djukanovic,‡ Maximilian A. Ganiek,† Benjamin Martin,†
Berthold Schenkel,† and Paul Knochel*
̈
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich, Germany
S
* Supporting Information
ABSTRACT: A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds
at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature
collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout,
the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention
of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.
he preparation of polyfunctional ketones using the
Tselective acylation of Grignard reagents with acid
chlorides, Weinreb amides, and related activated carbonyl
groups is well established.1,2 A drawback of such acylations can
be the moderate stability as well as the poor commercial
availability of activated acyl derivatives. In contrast, ethyl esters
of type 1 are readily available and are stable under a wide range
of conditions. However, their acylation with organomagnesium
reagents R2MgX (2) is often complicated by a facile secondary
reaction of the produced ketones 3 with the Grignard reagent
present in solution, leading to undesired tertiary alcohols of
type 4 (Scheme 1).3
are required in batch reactions for controlling the reaction
selectivity.5
Yoshida showed that functionalized ketones can be prepared
in continuous flow by the reaction of strongly activated acid
chlorides with organolithium reagents using extremely fast
micromixing.6 Also lithium organometallics react with dialkyl
oxalates to selectively produce α-keto-esters in continuous
flow.7
Herein, we report a selective acylation of various classes of
esters with Grignard reagents at convenient temperatures (−5
to 25 °C). In preliminary experiments, we have examined the
preparation of p-anisyl trifluoromethyl ketone 6a by the
reaction of ethyl trifluoroacetate (7) with p-anisylmagnesium
bromide (2a) (Scheme 2). Performing this reaction in batch
by slowly adding the Grignard reagent 2a to ethyl
trifluoroacetate (7, 1.0 equiv in THF) at −78 °C within 1
min, followed by a reaction time of 2 min, provides the desired
ketone 6a in 50% calibrated GC yield as well as 10% of the
tertiary alcohol 8 (Table 1, entry 1). Extending the reaction
time (3 h) increased the conversion only to a small extent,
improving the GC yield of 6a to 66% (entry 2). Performing the
reaction in batch at −5 °C led to an improved conversion but
produced a mixture of 6a and 8, showing clearly the limitation
of the batch process at elevated temperatures (entry 3).
Next, we investigated the reaction performance in a
commercial flow setup. After optimization of several reaction
conditions such as residence time (tr), reaction temperature,
Scheme 1. General Reaction of Organomagnesium Reagents
of Type 2 with Ethyl Esters of Type 1
The performance of organometallic reactions in continuous
flow may have considerable advantages since it allows us to
control the generation of organometallic intermediates more
accurately.4 For the above shown acylation, it may allow the
generation and consumption of the tetrahedral magnesiated
hemiacetal of type 5 in a controlled manner and therefore
avoid the imminent formation of the tertiary alcohol 4. Also,
such a setup would allow us to avoid low temperatures which
Received: November 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bromide furnished 6c in a higher yield of 75%, presumably due
to a chelating effect of the methoxy group, which leads to a
further stabilization of the tetrahedral intermediate of type 5.
Other Grignard reagents bearing various electron-donating
groups were also converted into the corresponding ketones
6d−f in 62−69% yield. Additionally, reaction of heteroar-
ylmagnesium bromide prepared from 2-bromobenzothiophene
via magnesium insertion reaction led to the heteroaryl ketone
6g in 74% yield. The indolyl ketone 6h was obtained in 84%
yield, using a temperature of 0 °C. Moreover, an organo-
magnesium reagent containing a sensitive ester group was also
a suitable substrate and gave the polyfunctional ketone 6i in
71% yield. The stabilization of the tetrahedral intermediate 5
by the electron-poor ester group allowed the use of a higher
reaction temperature of 15 °C.
Scheme 2. Synthesis of Trifluororo Ketones 6a−i Using
Ethyl Trifluoroacetate (7) and Grignard Reagents
In order to extend the scope of esters substrates for such
acylation reactions in continuous flow, N-heterocyclic esters of
type 9 were examined. These esters were especially selected for
providing a stabilizing coordinating effect on the tetrahedral
intermediate 5. Thus, m-anisylmagnesium bromide was mixed
with ethyl 2-picolinate (9a) in continuous flow at room
temperature for 10 min using an overall flow rate of 2 mL·
min−1, yielding the 2-pyridyl ketone 10a in 75% yield (Scheme
3). Reaction of the ester 9a with the electron-poor p-
Scheme 3. Synthesis of Heteroaryl Ketones 10a−g Using N-
a
Heterocyclic Esters of Type 9 and Grignard Reagents
a
b
c
−5 °C reaction temperature. 0 °C reaction temperature. 15 °C
reaction temperature.
Table 1. Batch/Flow Comparison for the Formation of p-
Anisyl Trifluoromethyl Ketone 6a and the Undesired
Tertiary Alcohol 8
conversion
yield 6a
d
yield 8
d
a
b
c
entry
setup
[°C] [min]
[%]
[%]
[%]
e
1
2
3
4
batch
batch
batch
−78
−78
−5
2
180
2
2
b
71
83
92
90
50
66
37
72
10
9
27
8
e
e
f
flow
−5
a
c
Reaction temperature. Reaction time. Conversion of 2a
determined by GC analysis of anisole compared to an internal
d
a
b
standard. Calibrated GC yield of 6a and 8 using tetradecane as the
0 °C reaction temperature. Methyl ester was used instead of ethyl
e
c
internal standard. Batch reactions were carried out in a 0.5 mmol
ester. 40 min residence time.
scale, and the Grignard reagent 2a was added dropwise over 1 min.
f
For optimization of the continuous flow procedure, see the
Supporting Information.
cyanophenylmagnesium bromide furnished the corresponding
ketone 10b in 77% yield. Even despite their destabilizing effect
on the intermediate 5, alkylmagnesium bromides were good
substrates in the reaction with ethyl 2-picolinate (9a) under
flow conditions, leading to alkylpyridyl ketone 10c in 63%
yield. Pyrazine esters like methyl 2-pyrazinecarboxylate (9b)
were also suitable substrates for this acylation procedure.
Several organomagnesium reagents reacted well with the
pyrazine ester 9b, producing the desired heteroaryl ketones
10d−f in 51−64% yield. Additionally, pyrimidinyl ketone 10g
was obtained in 60% yield using methyl pyrimidine-2-
and stoichiometry,8 a conversion of 90% was achieved, and the
desired ketone 6a was obtained in 72% GC yield accompanied
by only 8% of 8 (entry 4).
With these optimized conditions in hand, a range of valuable
trifluoromethyl ketones were prepared.9 Thus, the reaction of
m- and p-anisylmagnesium bromide with ethyl trifluoroacetate
(7) was complete after a residence time (tr) of 2 min at −5 °C
in THF using an overall flow rate of 10 mL·min−1, producing
the anisyl trifluoromethyl ketones 6a−b in 65−69% isolated
yield (Scheme 2). Interestingly, the use of o-anisylmagnesium
B
DOI: 10.1021/acs.orglett.9b04254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carboxylate (9c) and the corresponding Grignard reagent and
an extended residence time of 40 min.
Scheme 5. Synthesis of Bisaryl Ketones 15a−i Using Alkoxy
Esters of Type 13 and Grignard Reagents
Having the utility of α-keto esters in organic synthesis in
mind,10 we included diethyl oxalate 11 in our scope of
electrophiles. Thus, various α-keto esters were obtained at
room temperature within 10 min using an overall flow rate of 2
mL·min−1 (Scheme 4). Thus, the use of electron-rich Grignard
Scheme 4. Synthesis of α-Keto Esters 12a−e Using Diethyl
Oxalate (11) and Grignard Reagents
times was developed using commercially available ester starting
materials and readily accessible organomagnesium reagents.
This procedure is applicable to ethyl trifluoroacetate, diethyl
oxalates, and N-heterocyclic esters, leading to various function-
alized ketones. Moreover, bisaryl ketones were obtained in
satisfactory yields from esters without an ortho-stabilization
heteroatom by using magnesiated derivaties of 2-hydroxyethyl
esters.
reagents led to the desired α-keto esters 12a−b in 63−83%
yield. Also, fluorine-containing compounds 12c−d were
produced in 69−79% yield. Furthermore, a trifluoromethyl-
substituted organomagnesium reagent was used, affording the
α-keto ester 12e in 65% yield.
Notably, the coordinating effect proved beneficial for the
stabilization of the tetrahedral intermediate 5 and hence for
selective ketone formation.1a,c,h,kAfter extensive experimenta-
tions, it was found that 2-hydroxyethyl esters of type 13,
bearing an alkoxy group for coordination in an intermediate of
type 15, are useful reagents for the otherwise elusive formation
of bisaryl ketones (Scheme 5). The alkoxy group was
generated by mixing iPrMgCl·LiCl (1.05 equiv)11 and the
corresponding ethylene glycol monoester at 0 °C in THF for 5
min in batch. Thus, reaction of Grignard reagents of type 2
with these new ester electrophiles in flow enabled a selective
reaction producing bisaryl ketones 16a−b in 62−78% yield.
For comparison, using ethyl benzoate for the reaction with o-
anisylmagnesium bromide in continuous flow provides only
10% of the desired product 16a and a large amount of double
addition. Furthermore, halogenated alkoxybenzoates (14b−d)
were suitable substrates for this acylation protocol, leading to
chloro-substituted aryl ketones 16c−d in 62−74% yield,
difluoroaryl ketones 16e−f in 63−79% yield, and the
bromoaryl ketone 16g in 81% yield. Moreover, the cyano-
substituted ester in reaction with o-tolylmagnesium bromide
provides the bis-substituted ketone 16h in 68% yield.
Interestingly, the 3-pyridyl ketone 16i was afforded in 63%
yield by using the 3-pyridyl ester derivatives of type 14, which
was not possible using the regular ethyl nicotinate of type 9.
In summary, a selective acylation in continuous flow at
convenient temperatures (−5 to 25 °C) and short reaction
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04254.
1
Full experimental details and H, 19F, and 13C spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
Benjamin Martin: 0000-0001-6272-1653
Paul Knochel: 0000-0001-7913-4332
Present Address
†Novartis Pharma AG, Postfach, 4002 Basel, Switzerland.
Author Contributions
‡B.H. and D.D. contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b04254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) (a) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun.
2004, 2288−2289. (b) Ziegler, D. S.; Karaghiosofff, K.; Knochel, P.
Angew. Chem., Int. Ed. 2018, 57, 6701−6704.
ACKNOWLEDGMENTS
■
We thank Albermarle (Hoechst, Germany) and BASF for the
gift of chemicals. B.H. thanks Novartis Pharma AG for the
fellowship.
REFERENCES
■
(1) (a) Nahm, S.; Weinreb, M. S. Tetrahedron Lett. 1981, 22, 3815−
3818. (b) Bergbreiter, D. E.; Killough, J. M. J. Org. Chem. 1976, 41,
2750−2753. (c) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1974, 47, 1777−1780. (d) Wattanasin, S.; Kathawala,
F. G. Tetrahedron Lett. 1984, 25, 811−814. (e) Fujisawa, T.; Iida, S.;
Uehara, H.; Sato, T. Chem. Lett. 1983, 12, 1267−1270. (f) Fujisawa,
T.; Mori, T.; Sato, T. Tetrahedron Lett. 1982, 23, 5059−5062.
(g) Anderson, M. W.; Jones, R. C. F.; Saunders, J. J. Chem. Soc., Chem.
Commun. 1982, 5, 282−283. (h) Mattson, M. N.; Rapoport, H. J. Org.
Chem. 1996, 61, 6071−6074. (i) Evans, D. A.; Borg, G.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2002, 41, 3188−3191. (j) Park, J. K.; Shin, W.
K.; An, D. K. Tetrahedron Lett. 2013, 54, 3199−3203. (k) Knudsen,
C. G.; Rapoport, H. J. Org. Chem.1983, 48, 2260−2266.
(2) For transition-metal catalysis on selective preparation of ketones
see: (a) Lutter, F. H.; Grokenberger, L.; Hofmayer, M. S.; Knochel, P.
Chem. Sci. 2019, 10, 8241−8245. (b) Li, H.; Xu, Y.; Shi, E.; Wei, W.;
Suo, X.; Wan, X. Chem. Commun. 2011, 47, 7880−7882. (c) Milstein,
D.; Stille, J. K. J. Org. Chem. 1979, 44, 1613−1618. (d) Shi, S.;
Lalancette, R.; Szostak, R.; Szostak, M. Org. Lett. 2019, 21, 1253−
1257. (e) Meng, G.; Szostak, M. Org. Lett. 2018, 20, 6789−6793.
(f) Li, G.; Shi, S.; Lei, P.; Szostak, M. Adv. Synth. Catal. 2018, 360,
1538−1543. (g) Wu, X.; Neumann, H.; Beller, M. Chem. Soc. Rev.
2011, 40, 4986−5009. (h) Schranck, J.; Wu, X.; Neumann, H.; Beller,
M. Chem. - Eur. J. 2012, 18, 4827−4831.
(3) Whitmore, F. C.; Forster, W. S. J. Am. Chem. Soc. 1942, 64,
2966−2968.
́
(4) (a) Odille, F. G. J.; Stenemyr, A.; Ponten, F. Org. Process Res.
Dev. 2014, 18, 1545−1549. (b) Webb, D.; Jamison, T. F. Org. Lett.
2012, 14, 568−571. (c) Fukuyama, T.; Chiba, H.; Kuroda, H.;
Takigawa, T.; Kayano, A.; Tagami, K. Org. Process Res. Dev. 2016, 20,
503−509. (d) Hafner, A.; Mancino, V.; Meisenbach, M.; Schenkel, B.;
Sedelmeier, J. Org. Lett. 2017, 19, 786−789. (e) Stueckler, C.;
Hermsen, P.; Ritzen, B.; Vasiloiu, M.; Poechlauer, P.; Steinhofer, S.;
Pelz, A.; Zinganell, C.; Felfer, U.; Boyer, S.; Goldbach, M.; De Vries,
A.; Pabst, T.; Winkler, G.; LaVopa, V.; Hecker, S.; Schuster, C. Org.
Process Res. Dev. 2019, 23, 1069−1077. (f) Ganiek, M. A.; Becker, M.
R.; Berionni, G.; Zipse, H.; Knochel, P. Chem. - Eur. J. 2017, 23,
10280. (g) Weidmann, N.; Ketels, M.; Knochel, P. Angew. Chem., Int.
Ed. 2018, 57, 10748−10751. (h) McQuade, D. T.; Seeberger, H. J.
Org. Chem. 2013, 78, 6384−6389. (i) Chen, Y.; Hone, C. A.;
Gutmann, B.; Kappe, C. O. Org. Process Res. Dev. 2017, 21, 1080−
1087. (j) Price, G. A.; Hassan, A.; Chandrasoma, N.; Bogdan, A. R.;
Djuric, S. W.; Organ, M. G. Angew. Chem., Int. Ed. 2017, 56, 13347−
13350. (k) Teci, M.; Tilley, M.; McGuire, M. A.; Organ, M. G. Org.
Process Res. Dev. 2016, 20, 1967−1973. (l) Newby, J. A.; Blaylock, D.
W.; Witt, P. M.; Turner, R. M.; Heider, P. L.; Harji, B. H.; Browne, D.
L.; Ley, S. V. Org. Process Res. Dev. 2014, 18, 1221−1228.
(5) (a) Creary, X. J. Org. Chem. 1987, 52, 5026−5030. (b) Yamazaki,
T.; Terajima, T.; Kawasaki-Taskasuka, T. Tetrahedron 2008, 64,
2419−2424. (c) Rambaud, M.; Bakasse, M.; Duguay, G.; Villieras, J.
Synthesis 1988, 7, 564−566.
(6) (a) Nagaki, A.; Sasatsuki, K.; Ishiuchi, S.; Miuchi, N.; Takumi,
M.; Yoshida, J. Chem. - Eur. J. 2019, 25, 4946−4950. (b) Moon, S.;
Jung, S.; Bin Kim, U.; Kim, W. RSC Adv. 2015, 5, 79385.
(7) Nagaki, A.; Ichinari, D.; Yoshida, J. Chem. Commun. 2013, 49,
3242−3244.
(8) For further information see Supporting Information.
(9) For batch procedures for trifluoromethyl ketone formation see:
(a) Funabiki, K.; Hayakawa, A.; Inuzuka, T. Org. Biomol. Chem. 2018,
16, 913−918. (b) Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash,
G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. 1998, 37, 820−821.
(10) Eftekhari-Sis, B.; Zirak, M. Chem. Rev. 2015, 115, 151−264.
D
DOI: 10.1021/acs.orglett.9b04254
Org. Lett. XXXX, XXX, XXX−XXX