An improved procedure for the Beckmann rearrangement of cyclobutanones

Article abstract of DOI:10.1016/j.tetlet.2018.03.012

γ-Lactams are important building blocks for the synthesis of biologically active molecules and can easily be accessed via Beckmann rearrangement of cyclobutanones. However, Beckmann fragmentation is often a competing reaction for these strained ketones. We found that performing the Beckmann rearrangement with Tamura's reagent in the presence of aqueous HCl suppresses the undesired fragmentation reaction. This improved procedure was applied to a broad scope of substrates affording monocyclic, bicyclic, tricyclic or spirocyclic lactams. Our experimental results and DFT calculations suggest that the mechanism of the rearrangement probably involves a tetrahedral intermediate and doesn't proceed via oxime fragmentation as in a classical Beckmann rearrangement.

Full text of DOI:10.1016/j.tetlet.2018.03.012

Accepted Manuscript
An improved procedure for the Beckmann rearrangement of cyclobutanones
Mathilde Lachia, François Richard, Raphael Bigler, Amandine Kolleth-Krieger,
Michael Dieckmann, Alexandre Lumbroso, Ulfet Karadeniz, Saron Catak, Alain
De Mesmaeker
PII:
S0040-4039(18)30309-5
https://doi.org/10.1016/j.tetlet.2018.03.012
TETL 49781
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 January 2018
2 March 2018
5 March 2018
Please cite this article as: Lachia, M., Richard, F., Bigler, R., Kolleth-Krieger, A., Dieckmann, M., Lumbroso, A.,
Karadeniz, U., Catak, S., De Mesmaeker, A., An improved procedure for the Beckmann rearrangement of
cyclobutanones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.012
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Leave this area blank for abstract info.
An improved procedure for the Beckmann rearrangement of cyclobutanones
Mathilde Lachia, François Richard, Raphael Bigler, Amandine Kolleth-Krieger, Michael Dieckmann,
Alexandre Lumbroso, Ulfet Karadeniz, Saron Catak and Alain De Mesmaeker
MSH, 3Å MS
MSH, 2M HCl
26 monocyclic, spirocyclic,
tricyclic examples

1
Tetrahedron Letters
An improved procedure for the Beckmann rearrangement of cyclobutanones
Mathilde Lachiaa, François Richarda, Raphael Biglera, Amandine Kolleth-Kriegera, Michael Dieckmanna,
Alexandre Lumbrosoa, Ulfet Karadenizb, Saron Catakb and Alain De Mesmaekera
a Syngenta Crop Protection, Schaffhauserstrasse, CH-4332 Stein, Switzerland
b Bogazici University, Department of Chemistry, Bebek, 34342 Istanbul, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
γ-Lactams are important building blocks for the synthesis of biologically active molecules and
can easily be accessed via Beckmann rearrangement of cyclobutanones. However, Beckmann
fragmentation is often a competing reaction for these strained ketones. We found that
performing the Beckmann rearrangement with Tamura’s reagent in the presence of aqueous HCl
suppress the undesired fragmentation reaction. This improved procedure was applied to a broad
scope of substrates affording monocyclic, bicyclic, tricyclic or spirocyclic lactams.
Available online
Keywords:
Our experimental results and DFT calculations suggest that the mechanism of the
rearrangement probably involves a tetrahedral intermediate and doesn’t proceed via oxime
fragmentation as in a classical Beckmann rearrangement.
Beckmann rearrangement
Beckmann fragmentation
Tamura’s reagent
Lactam
2009 Elsevier Ltd. All rights reserved.
Strigolactones
The acid-mediated rearrangement of oximes to
adjacent quaternary centers, ring strain as for
amides was discovered by Beckmann more than a example in four-membered rings or the presence of
century ago and is one of the oldest and most
familiar organic transformations.1a-c This reaction is
functional groups which could stabilize
a
carbocation are known to be factors increasing the
sometimes competing with
a
Beckmann
fragmentation product.1c,5
fragmentation1d where the oxime fragments to the
corresponding nitrile and olefin. Both reactions
have been applied in the synthesis of natural
products, but it is quite challenging to control the
During the course of our investigation of the
synthesis of strigolactones, we have developed a
rapid access to tricyclic lactones via a Baeyer-
Villiger oxidation of the cyclobutanone 1.6-8 In the
outcome of the reaction and the regioselectivity of meantime, we discovered that lactam analogues of
the transformation.2,3 The Schmidt reaction also
strigolactones are very potent germination
faces a similar problem of selectivity between a stimulants of the parasitic weed seeds Orobanche
rearrangement pathway and a fragmentation
pathway. Recently, in silico analysis of the Schmidt
reaction revealed a late bifurcation after the
transition state, making it difficult to predict the
outcome of the reaction.4 In the case of the
Beckmann reactions, there have been limited
computational studies but steric bulk as for example
Cumana.9 However, our initial attempts to access
the tricyclic lactam skeleton via Beckmann
rearrangement of the cyclobutanone 1
were
unsuccessful due to competing Beckmann
fragmentation (Scheme 1).
We report here our efforts to improve the access to
lactams10,11 via Beckmann rearrangement of
cyclobutanones and our investigations to suppress
———
 Corresponding author. Tel.: +41-62-866-0701; mathilde_denise.lachia@syngenta.com
 Corresponding author. Tel.: +41-62-866-0268; alain.de_mesmaeker@syngenta.com

2
Tetrahedron
the fragmentation side reaction. We have then
repeating the reaction, we noticed that the
formation of the lactam 5 was highly dependent on
the batch of MSH 4, which is isolated by
precipitation from TFA by addition of water
applied our optimized conditions to a broad scope
of cyclobutanones or other substrates known to be
sensitive to fragmentation. Our results also unveiled
that the mechanism of the rearrangement probably followed by filtration.17 Thus, we suspected that the
involves a tetrahedral intermediate and doesn’t
proceed via oxime fragmentation.
acid or water present in the MSH might play a key
role in the outcome of the reaction.
We first investigated the classical Beckmann
We investigated the role of water by adding an
rearrangement of oxime
2
obtained from excess of water or molecular sieves to the reaction
cyclobutanone 1. To our disappointment, only
fragmentation product 3 was isolated in 65% yield,
even when using mesitylene sulfonyl chloride
reported to favor rearrangement.12,13 There are
indeed few examples of rearrangement of oximes
(Table 1, entries 1-4). Water was increasing the
yield of the lactam whereas anhydrous conditions
favored the fragmentation product. We then looked
at the effect of different acids (Table 1, entries 5-7).
Trifluoroacetic acid or acetic acid didn’t reduced
derived from cyclobutanones to lactams via the fragmentation but aqueous HCl almost
Beckmann rearrangement.14 The rearrangement of
cyclobutanone has been mostly reported using O-
mesitylene sulfonylhydroxylamine (MSH 4,
Tamura’s reagent)15, in particular in the case of
completely suppressed the formation of the
undesired nitrile. Finally, the addition of 5
equivalents of 2M HCl provided the desired lactam
in 64% yield (Table 1, entry 9) but using more
fused cyclobutanone similar to our system.16 concentrated HCl solution (4M) did not proved to
Unfortunately, in our case, these optimized
conditions gave only 8% of the desired rearranged
lactam 5 with the fragmentation still occurring
during our first attempt (Scheme 1). This was not
totally unexpected as the release of ring strain in the
cyclobutanone and the stabilizing effect of the
phenyl ring would favor the formation of a benzylic
carbocation in the fragmentation pathway. When
be
beneficial
(entry
10).
Replacing
dichloromethane by methanol or THF didn’t give
any reaction as well as substituting MSH 4 with
hydroxylamine O-sulfonic acid was not possible
(Table 1, entries 11-15).18
b)
a)
2
3
c)
MSH 4
1
5
5'
3
Scheme 1: Beckmann rearrangement and fragmentation of cyclobutanone 1. Conditions: a) NH2OH.HCl,
NaOAc, MeOH, reflux, 83%; b) MesSO2Cl, LiOH, THF, 65%; c) see Table 1
Table 1. Optimization of the Beckmann rearrangement of cyclobutanone 1.
Entry
Conditions
Rearrangement
Fragmentation 3a
5+5‘a
1
2
3
4
5
6
7
8
4, DCM
35
55
28
9
27
21
38
68
9b
4, DCM, water (10 equiv)
4, DCM, Na2SO4
4, DCM, Molecular Sieve 3Å
4, DCM, TFA (1equiv)
4, DCM, AcOH (1equiv)
4, DCM, HCl 2M (1 equiv)
4, DCM, HCl 2M (2 equiv)
27
20
60
60
39
32
14

3
9
4, DCM, HCl 2M (5 equiv)
4, DCM, HCl 4M (5 equiv)
4, MeOH, HCl 4M (5 equiv)
4, THF, HCl 4M (5 equiv)
64c
6
17
-
10
11
12
13
14
15
50
11
traces
-
4, DCM, MS 3Å , Et3N (1.0 equiv)
-
-
-
-
NH2-OSO3H, DCM, HCl 2M (5 equiv)
NH2-OSO3H, DCM
-
-
a isolated yield; b hydration of the olefin was also observed probably due to a quench of the carbocation (17%); c formation of regioisomer 5’ was also observed,
Regioisomer ratio (rr) = 11/1.
.
Taken together, these results suggest that the
reaction proceeds via the formation of a tetrahedral
intermediate 6 that undergoes a rearrangement,
Stationary points were identified as ground state or
transition state by normal mode analysis. All free
energies were reported at 1 atm and 298 K. The
similarly to a Baeyer-Villiger reaction (Scheme 2). formation of intermediate 6 from reactant 1 and
A similar mechanism was already proposed in the
case of camphor.18 Recently, White et al. have also
reported the addition of acetic acid to favor the
fragmentation of oxime sulfonate during the
synthesis of (+)-codeine.3 In our case, we propose
that the acid might promote the addition of MSH to
the cyclobutanone 1 and the elimination of
mesitylene sulfonic acid, similarly as in a Baeyer-
Villiger reaction. Under anhydrous conditions,
intermediate 6 eliminates water to give the oxime
MSH as well as the three competing routes leading
to oxime sulfonate, and the regioisomeric lactams 5
and 5ʹ, were computationally modelled and
energetically compared to identify the most
plausible route (Figure 1).
TSo
28.3
TS6
TS5'
17.8
18.7
sulfonate,
which
undergoes
mainly
the
fragmentation product. Surprisingly, triethylamine
completely inhibits the reaction, probably slowing
down the addition of MSH to the cyclobutanone 1.
Deactivation of the cyclobutanone 1 due to acetal
formation probably explains as well why the
reaction doesn’t proceed in methanol or THF. Thus,
water and acid play an essential role in favoring the
formation of 6 and preventing the formation of the
oxime sulfonate.
TS5
16.2
1+4
0
6
-7.0
oxime
-5.1
5 Int
-78.7
5' Int
-80.8
Computational Rationalization
A density functional theory (DFT) approach has
been utilized for the computational investigation of
the possible reaction mechanisms in Scheme 1. All
geometry optimizations and frequency calculations
were performed in the gas phase. A meta-GGA
functional M06-2X,19,20 implemented in the
Gaussian 09 (G09) program package21 was utilized,
together with the 6-31+G(d,p) basis set, due to its
good performance in organic systems with
dispersion effects.22-24 The effect of the solvent
environment was taken into account utilizing
implicit solvation (IEF-PCM)25 in water. Moreover,
catalytic water molecules were introduced in an
explicit manner. Intrinsic reaction coordinate (IRC)
analysis were conducted at each transition state to
verify the corresponding reactant and product.26-28
Figure 1. Free energy profile for the water-assisted
formation of oxime sulfonate and regioisomeric
lactams 5 and 5ʹ (M06-2X/6-31+G(d,p), IEF-PCM
in water, free energies in kcal mol-1)
Intermediate 6 was formed through an activation
barrier of 18.7 kcal mol-1 in a concerted fashion.
Whereas the formation of the lactams was shown to
proceed through a stepwise mechanism, the first
step involving the ring expansion, which is
incidentally the rate determining step followed by a
second step in which the proton transfer occurs
(proton transfer steps not depicted in Fig 1). The
oxime sulfonate, however, formed through a
concerted mechanism from intermediate 6. Free

4
Tetrahedron
energy barriers depict the favorable formation of
regioisomeric lactams 5 and 5ʹ. The role of water
activation when compared to 5 and 5ʹ. The
reactions leading to the lactam were found to be
assistance was shown to be crucial in obtaining the highly exergonic and resulting in very stable
rearrangement products. Water molecules act as
catalysts, stabilizing transition states (Fig 2) and
lowering the activation barriers in favor of the
lactam products. These results are in line with
experimental findings where anhydrous conditions
products in line with the experiments.
With our optimized conditions in hand, we
investigated the rearrangement of other tricyclic
cyclobutanones with different electron donating and
withdrawing substituents on the aromatic ring
lead to the fragmentation reaction. The rate (Scheme 3). The cyclobutanones were prepared by
determining transition state (TS) structures for the
intramolecular [2+2]-cycloaddition of ketene-
iminium salts generated from the corresponding
formation of intermediate 6 (TS6) oxime (TSO), 5
(TS5), and 5ʹ (TS5’) are depicted in Figure 2. The diisopropyl amides as reported previously.6,7 (see
results indicate that the formation of the oxime
sulfonate is unlikely with a higher free energy of
supporting information)
TS6
TSO
TS5
TS5ʹ
Figure 2. Optimized transition state (M062X/6-31+G(d,p)) structures for the formation of intermediate 6
and three alternative pathways (critical distances in Å).
7
3
H2O
MSH
1
6
5
5'
Scheme 2: Proposed mechanism for the ring expansion mediated by MSH
The lactams 5a-5l were obtained in good yield and
good selectivity, the insertion at the benzylic
position being electronically favored. It is
noteworthy to mention that thiophene derived

5
cyclobutanone building block 1j was efficiently
prepared from 8 in 4 steps as depicted in Scheme 4
In the case of electron withdrawing groups on the
aryl ring, yields were usually higher but formation
of the other regioisomer was increased. Electron
donating groups in 5c and 5e still gave only the
rearrangement product, despite the carbocation 7
being highly stabilized in the fragmentation
pathway. In addition, even in the case of hindered
cyclobutanone, the desired lactams 5l was isolated
as the only product of the reaction (Scheme 3,
method A), whereas the original conditions with
MSH in dichloromethane gave mostly the
fragmentation compound (Scheme 3, method B).
We then looked at the reaction of different
monocyclic or bicyclic cyclobutanones which were
either commercially available or reported in the
literature (Scheme 5). Lactams 5n-5v were obtained
in good yield and good regioselectivity except in
the case of bicyclic lactam 5u and 5v. We were
pleased to find that the fragmentation didn’t occur,
even in the case of bulky spiro derivatives 5n, 5o
and 5t nor in the case of benzylic systems such as
5r and 5s where the formation of a carbocation in
the fragmentation pathway would be highly
favored. Finally, we tested our conditions on the
commercial 2,2-dimethylcyclohexanone and 2,2-
dimethylcyclopentanone which cleanly gave the
corresponding lactams 5w and 5x whereas the
presence of a quaternary center adjacent to the
starting oxime is known to give a substantial
amount of fragmentation during Beckmann
A: 84%
rr: 17/1
A: 60%
rr=15/1
A: 57%
rr>20/1
A: 55%
rr: 15/1
5a
5b
5c
5d
A: 56%
rr>20/1
A: 80%
rr: 10/1
A: 63%
rr=4.5/1
A: 61%
rr>20/1
5e
5f
5g
5h
A: 89%
rr: 14/1
B: 62%
rr>20/1
A: 53%; rr>20/1
B: 49%
5i
5j
5k*
A: 73%; rr>20/1
B: 21% (61% fragmentation)
B: 68%
5m**
5l*
Scheme 3: Synthesis of different tricyclic lactams
from their corresponding tricyclic cyclobutanones
via improved Beckmann procedure. Reaction
conditions: Method A: MSH 4, 2 M HCl (5 equiv),
CH2Cl2, 12 h; Method B: MSH 4, CH2Cl2, 12 h; rr
refers to the regioisomeric ratio between the
corresponding lactam 5 and 5ʹ; *Cyclobutanones
were prepared as in ref 7; **Cyclobutanone was
prepared as in ref 8.
rearrangement.1
The
conditions
of
the
1- NBS, AcOH
CHCl3, 0°C, 94%
rearrangement were also compatible with some
sensitive functional groups such as ester and Boc
protecting group as is 5o, 5p and 5t, respectively.
2- AllSnBu3, Pd(PPh3)4
LiCl, DMF, 100°C, 79%
3- NaOH, dioxane/H2O
8
9
50°C, 95%
Pyrrolidine
EDCI/HOAt, Et3N
In conclusion, we have identified new and practical
DMF, 60°C, 70%
reaction
conditions
for
the
Beckmann
rearrangement of cyclobutanones which reduce or
suppress the formation of undesired fragmentation
products. The broad scope of these conditions was
illustrated on monocyclic, spirocyclic, bicyclic and
tricyclic lactams and challenging hindered
substrates. We postulate that the reaction proceed
mainly via a tetrahedral intermediate and not via
the oxime rearrangement.
Tf2O, collidine, CH2Cl2
r.t.
Then CCl4/H2O, 70°C
76%
1j
10
Scheme 4: Synthesis of cyclobutanone precursor 1j

6
Tetrahedron
11. Screpanti, C.; Fonné-Pfister, R.; Lumbroso, A.; Rendine, S.;
Lachia, M.; De Mesmaeker, A. Bioorg. Med. Chem. Lett. 2016,
26, 2392.
12. Cymerman Craig, J.; Naik, A. R. J. Am. Chem. Soc. 1962, 84,
3410.
13. Conley, R.T.; Annis, M. C. J. Org. Chem. 1962, 27, 1961.
14. a) Umbreen, S.; Linker, T. Chem. Eur. J. 2015, 21, 7340; b)
Błaszczyk, K.; Koenig, H.; Mel, K.; Paryzek, Z. Tetrahedron
2006, 62, 1069; c) Błaszczyk, K.; Paryzek, Z.; Liebiegs Ann.
Chem. 1993, 1105.
A: 84%
A: 51%
A: 69%
A: 59%
5n
5o
5p
5q
15. Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1.
16. a) Bartmann, W.; Beck, G.; Knolle, J.; Rupp, R. H.; Tetrahedron
Lett. 1982, 23, 3647; b) Luh, T.-Y.; Chow, H.-F.; Leung, W. Y.;
Tam, S. W. Tetrahedron 1985, 41, 519; c) Rimböck, K.-H.;
Pöthig, A.; Bach, T. Synthesis 2015, 47, 2869; d) Li, X.;
Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 11004; e)
Ghosez, L.; Yang, G.; Cagnon, J. R.; Le Bideau, F.; Marchand-
Brynaert, J. Tetrahedron 2004, 60, 7591; f) Lumbroso, A.; Catak,
S.; Sulzer-Mossé, S.; De Mesmaeker, A. Tetrahedron Lett. 2014,
55, 5147.
A: 50%
1/1 mixture of regioisomers
A: 72%
A: 88%
A: 70%
5u'
5r
5s
5t
5u
17. Javier Mendiola, J.; Rincón, J. A.; Mateos, C.; Soriano, J. F.; de
Frutos, Ó.; Niemeier, J. K.; Davis. E. M. Org. Process Res. Dev.
2009, 13, 263.
18. a) Krow, G. R.; Szczepanski, S. Tetrahedron Lett. 1980, 21,
4593; b) Krow, G. R.; Szczepanski, S. J. Org. Chem. 1982, 47,
1153; c) Krow, J. R.; Cheung, O. H.; Hu, Z.; Lee, Y. B. J. Org.
Chem. 1996, 61, 5574.
19. Zhao, Y., Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
20. Zhao, Y., Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
21. M. J. Frisch et al., Gaussian 09, Revision E.01, Gaussian, Inc., W.
C. 2013.
n
n = 0, A: 68%; rr>20/1, 5w
n = 1, A: 63%; rr>20/1, 5x
A: 70%
7/3 mixture of regioisomers
5v 5v'
22. Mollet, K., Catak, S., Waroquier, M., Van Speybroeck, D’hooghe,
M., De Kimpe, N. J. Org. Chem. 2011, 76, 8364.
23. Catak, S., Hemelsoet, K. Hermosilla, L., Waroquier, M., Van
Speybroeck, V. Chem. Eur. J. 2011, 17, 12027.
24. Goossens, H., Winne, J. M., Wouters, S., Hermosilla, L., De
Clercq, P. J, Waroquier, M., Van Speybroeck, V., Catak, S. J.
Org. Chem. 2015, 80, 2609.
Scheme 5: Synthesis of different lactams from their
corresponding cyclobutanones via improved
Beckmann procedure. Reaction conditions: Method
A: MSH 4, 2 M HCl (5 equiv), CH2Cl2, 12 h;
Isolated yields are reported. A single regioisomer
was observed unless mentioned otherwise.
25. Fukui, K. Acc. Chem. Res. 1981, 14, 363.
26. Hratchian, H. P., Schlegel, H. B. J. Chem. Phys. 2004, 120, 9918.
27. Hratchian, H. P., Schlegel, H. B. J. Chem. Theory Comput. 2005,
1, 61.
Acknowledgments
We would like to thank Nicola Compagnone for his
openness and the discussion on the reaction
conditions and for initial experiments.
References and notes
1.
a) Beckmann, E Ber. Dtsch. Chem. Ges.1886, 19, 988; b)
Chandrasekhar, S., In Comprehensive Organic Synthesis (2nd
Edition), Knochel, P.; Molander, G. A., Eds.; Elsevier, 2014; Vol
7, pp 770-800; c) Gawley, R. E. In Organic Reactions; John Wiley
& Sons, Inc, 1988; Vol 35, pp 1-420; d) Drahl, M. A.; Manpadi,
M.; Williams, L. J. Angew. Chem. Int. Ed. 2013, 52, 11222.
Hutt, O. E.; Doan, T. L.; Georg, G. I. Org. Lett. 2013, 15, 1602.
White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64,
7871.
2.
3.
4.
5.
6.
7.
8.
9.
Akimoto, R.; Tokugawa, T.; Yamamoto, Y.; Yamataka, H. J. Org.
Chem. 2012, 77, 4073.
Nguyen, M. T.; Raspoet, G.; Vanquickenborne, L. G. J. Am.
Chem. Soc. 1997, 119, 2552.
Lachia, M; Jung, P. M. J.; De Mesmaeker, A. Tetrahedron Lett.
2012, 53, 4514.
Lachia, M; Wolf, H. C.; De Mesmaeker, A. Bioorg. Med. Chem.
Lett. 2014, 24, 2123.
Lachia, M.; Dakas, P.-Y.; De Mesmaeker, A. Tetrahedron Lett.
2014, 55, 6577.
Lachia, M.; Wolf, H. C.; Jung, P. J. M.; Screpanti, C.; De
Mesmaeker, A. Bioorg. Med. Chem. Lett. 2015, 25, 2184.
10. Lumbroso, A.; Villedieu-Percheron, E.; Zurwerra, D.; Screpanti,
C.; Lachia, M.; Dakas, P.-Y.; Castelli, L.; Paul, V.; Wolf, H. C.;
Sayer, D.; Beck, A.; Rendine, S.; Fonné-Pfister, R.; De
Mesmaeker, A. Pest Manag. Sci. 2016, 72, 2054.

7



An improved procedure for the Beckmann
rearrangement of cyclobutanones has been
developed
Experiments and DFT calculation support a
rearrangement mechanism involving a
tetrahedral intermediate
The generality of the method has been
illustrated on 26 examples.