Propylphosphonic anhydride (T3P) mediated synthesis of β-lactams from imines and aryl-substituted acetic acids

Article abstract of DOI:10.1016/j.tetlet.2015.01.009

β-Lactams were prepared from imines and aryl-substituted acetic acids using T3P as an activating agent. In most cases, good to excellent yields were obtained (up to 93%) and the trans-β-lactam was the exclusive or major diastereoisomer (confirmed through

Full text of DOI:10.1016/j.tetlet.2015.01.009

Accepted Manuscript
Propylphosphonic anhydride (T3P) mediated synthesis of β-lactams from
imines and aryl-substituted acetic acids
Graeme Coulthard, William P. Unsworth, Richard J.K. Taylor
PII:
S0040-4039(15)00012-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.009
TETL 45678
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 November 2014
18 December 2014
2 January 2015
Please cite this article as: Coulthard, G., Unsworth, W.P., Taylor, R.J.K., Propylphosphonic anhydride (T3P)
mediated synthesis of β-lactams from imines and aryl-substituted acetic acids, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.01.009
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Propylphosphonic anhydride (T3P) mediated
synthesis of β-lactams from imines and
aryl-substituted acetic acids
Leave this area blank for abstract info.
Graeme Coulthard∗, William P. Unsworth, Richard J. K. Taylor∗

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Propylphosphonic anhydride (T3P) mediated synthesis of β-lactams from imines and
aryl-substituted acetic acids
Graeme Coulthard∗, William P. Unsworth, Richard J. K. Taylor∗
Department of Chemistry, University of York, Heslington,York, YO10 5DD, U.K.
ARTICLE INFO
ABSTRACT
Article history:
Received
β-Lactams were prepared from imines and aryl-substituted acetic acids using T3P as an
activating agent. In most cases, good to excellent yields were obtained (up to 93%) and the
trans-β-lactam was the exclusive or major diastereoisomer (confirmed through analysis of 1H
NMR coupling constants and by X-ray crystallography).
Received in revised form
Accepted
Available online
Keywords:
β-lactams
T3P
2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Harry Wasserman: inspirational organic chemist and longtime
ambassador for Tetrahedron publications.
Imines
Direct imine acylation (DIA)
N-Acyliminium ions
ethyl chloroformate,18 and DMSO/Ac2O.19
1. Introduction
Propyl phosphonic anhydride (T3P) has been found to be an
β-Lactams
are
most
notably
associated
with
efficient activating agent for carboxylic acids in a range of
transformations.20-25 However, the use of T3P as an activating
agent for the synthesis of β-lactams from carboxylic acids and
imines has been limited. Vaid and co-workers have described the
T3P-mediated reaction of glycine Dane salt and a small selection
of α,β-unsaturated imines which gave cis-β-lactam products
[Scheme 1, eqn. (1)].26
naturally-occurring and man-made anti-bacterial agents including
penicillins, cephalosporins, monobactams, and carbapenams,1
which continue to be a bulwark against bacterial infections
despite rising resistance.2 In addition, they continue to be of
interest in the areas of pharmacology and medicinal chemistry
where research into novel anti-bacterial agents,3 their use as
antiviral agents,4 and their use as synthetic intermediates for
other useful targets is ongoing.5
Scheme 1. T3P-mediated synthesis of β-lactams from
carboxylic acids and imines.
Though there have been recent advances in the synthesis of β-
lactams,6-8 they are most commonly synthesized by the
Staudinger synthesis.9 This involves the reaction of a ketene,
which may be pre-formed or generated in situ, with an imine in a
formal [2+2]-cycloaddition reaction. The exact mechanism and
the reason for the stereochemical outcome of this reaction is the
subject of much discussion and can depend on a number of
factors including the substrate, reaction conditions, solvent,
temperature and the order of addition of reagents.10-13 Perhaps
still the most common method for the synthesis of β-lactams is
the reaction of acid chlorides with imines in the presence of a
base. This reaction is generally considered to proceed through a
ketene,13 but a mechanism involving the direct acylation of the
imine could also be possible in certain cases.14 A number of
reagents have been reported to successfully activate carboxylic
acids directly, also enabling the synthesis of β-lactams from
imines and carboxylic acids, rather than via acid chlorides; these
include Mukaiyama’s reagent,15-16 p-toluenesulfonyl chloride,17
Zarei recently reported the use of T3P for the synthesis of cis-
β-lactam products from imines and carboxylic acids,
———
∗ Corresponding author. Tel.: 44(0)1904 322606; e-mail: richard.taylor@york.ac.uk

2
Tetrahedron
predominantly carboxylic acids possessing
a
heteroatom
This was successful as when the BF3·OEt2 was omitted from
the reaction, no 6-membered ring product 3 was detected at all
and the major product, after 2 h, was the β-lactam 4a (39%) as
determined using the internal standard. This appeared to be the
trans-isomer 4a based on the coupling constant between the two
CH protons of the 4-membered ring (2.1 Hz) and no cis-
diastereoisomer could be detected.32
substituent in the α-position [Scheme 1, eqn. (2)].27 We now
report the T3P-mediated formation of trans-β-lactams from aryl-
substituted acetic acids and imines [Scheme 1, eqn. (2)].
2. Results and Discussion
We have recently reported on the use of T3P for the direct
acylation of imines with functionalized benzoic acids (direct
imine acylation, DIA) and the subsequent intramolecular trapping
of the resultant N-acyliminium ions with ortho-substituents on
the benzoic acids [Scheme 2, eqn. (1)].28 Subsequently, we
showed the scope of this methodology could be expanded to
aliphatic carboxylic acids containing nucleophiles or pro-
nucleophiles [Scheme 2, eqns. (2) and (3)],29 and have shown the
utility of this methodology in natural product synthesis.28,30-31
Using these conditions, but with a 20 h reaction time to ensure
complete reaction,33 we began to explore the scope of the
reaction (Table 1). β-Lactam 4a was obtained in 89% isolated
yield under these conditions, again as a single diastereoisomer.
This was confirmed to be the trans-isomer by single crystal
X-ray crystallography (Figure 1).34
Table 1. T3P-mediated formation of β-lactams, acid scope.
Scheme 2. Direct imine acylation (DIA) with carboxylic acids
for the formation of diverse heterocycles.
ortho
DIA with
-functionalised benzoic acids:
R
R
R
HX
HX
X
O
T3P
+
(1)
N
N
HO
N
O
NEt(i-Pr)2
O
X = O, NR, S
O
O
O
N
N
O
O
DIA with aliphatic acids containing O-, N-, and S- nucleophiles:
(±)-4b
(±)-4a
80% 2.9:1 trans:cis
89% trans only
R1X
HO
R2
R1X
N
R2
n
X
R2
T3P
+
(2)
N
N
n
n
S
NEt(i-Pr)2
X = O, NR, S
R1 = H or PG
O
O
S
O
N
N
N
O
O
O
DIA with aliphatic acids containing C- nucleophiles, e.g.
(±)-4c
(±)-4d
(±)-4e
80% 5.8:1 trans:cis
78% 3:1 trans:cis
78% 1:1.7 trans:cis
HN
HN
HN
O
T3P
(3)
+
N
HO
N
N
NEt(i-Pr)2
N
O
O
Br
N
N
O
O
N
O
During these direct imine acylation studies we investigated the
reaction of acyclic imine 1 with 3,4-dimethoxyphenylacetic acid
2 (Scheme 3). Under our standard DIA conditions [T3P, NEt(i-
Pr)2, CHCl3, 70 °C and then BF3·OEt2] the expected 6-membered
ring product 3 (40%) was formed, but β-lactam 4a was also
observed in fair yield (33%). The percentage of each product
present was determined by 1H-NMR spectroscopy after the
addition of an internal standard (1,3,5-trimethoxybenzene). Given
the presence of the β-lactam product we considered that it might
be possible to slightly alter our reaction conditions in order to
obtain β-lactam products exclusively.
(±)-4f
76% 7:1 trans:cis
(±)-4h
84% 13.2:1 trans:cis
(±)-4g
80% 6.2:1 trans:cis
Figure 1. X-ray crystal structure of trans-β-lactam 4a (50%
probability ellipsoids).
Scheme 3. The T3P mediated formation of β-lactams.a
A selection of aryl-substituted acetic acids were chosen as
substrates for the reaction with the commercially available imine
N-benzylidenemethylamine 1 (Table 1, 4b-4h). These reactions
all proceeded in good yield and with the trans-β-lactam as the
aReaction conditions: T3P (1.85 eq. of a 50% wt. solution in THF), NEt(i-Pr)2
(1.5 eq.), CHCl3, 70 °C, 1 h. Then: BF3·OEt2 (2.0 eq.), 70 °C, 1 h.

3
major diastereoisomer in most cases (4b-4d and 4f-4h). The
trans-selectivity ranged from 2.9:1 for 4b up to 13.2:1 for 4h.
This assignment of stereochemistry was again based on the
coupling constants of the two protons of the β-lactam ring which
were ~2.1 Hz in the trans-diastereoisomers (J = ~5.1 Hz for cis-
diastereoisomers). In addition, the spectroscopic data obtained for
compounds 4c and 4d were consistent with those reported in the
literature for these compounds.35-37 The one exception to the
trans-selectivity trend was the 2-thiophene-substituted product 4e
We found that
a
cyclic imine derived from
1,2,3,4-tetrahydroisoquinoline was also a suitable substrate with
novel product 4o isolated as solely the trans-β-lactam. Finally, a
C-alkyl substituted imine was explored. The resultant product 4p
was isolated in relatively low yield, but again, with the trans-β-
lactam as the major diastereoisomer.
In summary we have developed a T3P-mediated synthesis of
β-lactams from imines and aryl-substituted acetic acids. In the
majority of cases investigated the reactions are high yielding and
provide the trans-β-lactam as the major diastereoisomer. This is
complementary to T3P-mediated methods using heteroatom-
substituted acetic acids which give predominantly cis-β-lactams.
which was isolated as
a 1:1.7 trans:cis mixture. The
trans-selectivity observed in most cases might be explained by
existing diastereoselectivity models.12 Vaid and Zarei found that
cis-β-lactams were the major diastereoisomers when the
carboxylic acid was α-substituted with a heteroatom. It is
possible that the presence of this heteroatom aids a direct ring-
closure of the zwitterionic intermediate, leading to the
cis-products. In our case it is possible that the intermediate
undergoes isomerisation before ring-closure, thus leading to
Acknowledgments
The authors thank the EPSRC for postdoctoral support (G.C.,
EP/J016128/1), the University of York for support (W.P.U), and
Euticals for the generous donation of T3P. We are also grateful to
Dr Adrian C. Whitwood (University of York) for X-ray
crystallography.
predominantly
diastereoisomers.12
the
trans-β-lactams
as
the
major
The trans-selectivity continued when the imine scope was
investigated (Table 2, 4i-4p). The acid component for these
reactions was 3,4-dimethoxyphenylacetic acid and the required
acyclic imines were synthesized by reaction of the appropriate
amine with the appropriate aldehyde in CH2Cl2 with MgSO4 (see
Supporting Information for experimental details). 4-Methoxy-N-
[(E)-phenylmethylidene]aniline was a successful substrate as
product 4i was isolated in 83% yield and with exclusive
formation of the trans-product. A small selection of N-allyl
imines differing in the nature of the C-substitution were next
investigated and these gave the β-lactam products in high yields
(4j-4n). The trans:cis ratios ranged from 2:1 (4l), through 5.4:1
(4m) and 8:1 (4n), up to trans only (4j and 4k).
References and notes
1. For a review, see: The Organic Chemistry of β-Lactams; Georg,
G. I., Ed.; Verlag Chemie: New York, 1993.
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G.; Strynadka, N. C.; Walsh, T. R.; Coombes, B. K.; Wright, G.
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Table 2. T3P-mediated formation of β-lactams, imine scope
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O
O
O
O
O
O
O
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20, 2771–2774.
N
N
O
N
O
O
(±)-4j
O
(±)-4k
62% trans only
(±)-4i
83% trans only
75% trans only
O2N
O
NC
O
O
O
O
O
N
N
O
N
O
N
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Tetrahedron Lett. 2010, 51, 3002–3005.
O
(±)-4l
93% 2:1 trans:cis
(±)-4m
(±)-4n
97% 8:1 trans:cis
89% 5.4:1 trans:cis
21. Nagendra, G.; Madhu, C.; Vishwanatha, T. M.; Sureshbabu, V. V.
Tetrahedron Lett. 2012, 53, 5059–5063.
O
O
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2990–2996.
O
O
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2011, 13, 5048–5051.
N
N
O
O
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(±)-4o
61% trans only
(±)-4p
30% 3.8:1 trans:cis

4
Tetrahedron
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33. Procedure for the T3P mediated synthesis of β-lactams: The
appropriate imine (0.762 mmol) and carboxylic acid (0.915 mmol,
1.2 eq.) were dissolved in CHCl3 (4 mL). NEt(i-Pr)2 (246 µL,
1.410 mmol, 1.85 eq.) and then T3P [364 mg, 1.14 mmol, (728 mg
of 50% wt. solution in THF)] were added by syringe. The reaction
was stirred at 70 °C for 20 h. After cooling, the reaction mixture
was poured into sat. NaHCO3 (10 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure to give the crude
products. The diastereoisomeric ratio was determined by 1H-NMR
spectroscopy at this stage. The crude products were purified by
column chromatography on silica (see individual entries in the
Supporting Information for eluting conditions). All novel
compounds were fully characterised, see Supporting Information
for details.
34. X-ray data for compound 4a have been deposited with the
Cambridge Crystallographic Data Centre (CCDC 1032056)
which can be obtained free of charge at
www.ccdc.cam.ac.uk/data_request/cif
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37. Kim, I.; Roh, S. W.; Lee, D. G.; Lee, C. Org. Lett. 2014, 16,
2482–2485.
Supplementary Material
Supplementary material
(experimental
procedures,
1
characterization data, H and 13C spectra of novel compounds)
can be found online at