Generation and electrophile trapping of N -Boc-2-lithio-2-azetine: Synthesis of 2-substituted 2-azetines

Article abstract of DOI:10.1021/ol403626k

s-BuLi-induced α-lithiation-elimination of LiOMe from N-Boc-3-methoxyazetidine and further in situ α-lithiation generates N-Boc-2-lithio-2-azetine which can be trapped with electrophiles, either directly (carbonyl or heteroatom electrophiles) or after transmetalation to copper (allowing allylations and propargylations), providing a concise access to 2-substituted 2-azetines.

Full text of DOI:10.1021/ol403626k

Letter
pubs.acs.org/OrgLett
Generation and Electrophile Trapping of N‑Boc-2-lithio-2-azetine:
Synthesis of 2‑Substituted 2‑Azetines
David M. Hodgson,* Christopher I. Pearson, and Madiha Kazmi
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
*
S Supporting Information
ABSTRACT: s-BuLi-induced α-lithiation−elimination of
LiOMe from N-Boc-3-methoxyazetidine and further in situ
α-lithiation generates N-Boc-2-lithio-2-azetine which can be
trapped with electrophiles, either directly (carbonyl or
heteroatom electrophiles) or after transmetalation to copper (allowing allylations and propargylations), providing a concise
access to 2-substituted 2-azetines.
2
-Azetidinones (β-lactams) and azetidines are well-studied
azetine, in which the unsaturation retained in the adducts could
provide a site for further synthetic manipulation. Here we
communicate our promising preliminary results in this area.
While N-protection/activation with the thiopivaloyl group
had been found to be uniquely successful in enabling α-
lithiation−electrophile trapping of azetidine and 3-hydroxyaze-
four-membered azacyclic systems with important biological
activities. In contrast, the unsaturated and more strained 2-
azetine (1,2-dihydroazete) system 1 (Figure 1) is comparatively
less explored, which partly reflects issues of ease of access and
stability (notably the propensity to undergo 4e electrocyclic
ring-opening to 1-azabutadienes), although electron-withdraw-
1
4
,5
tidine, with 2-azetine 3 only modest isolated yields of trapped
products (∼15% using either MeI or BnBr) could be obtained
2
,3
ing groups on the nitrogen are known to reduce instability.
6
despite extensive experimental investigations. We therefore
turned our attention to alternative nitrogen protection.
Following pioneering studies by Beak and co-workers, Boc
protection now is well-established for facilitating α-lithiation−
7
2
Figure 1. 2-Azetine 1.
electrophile trapping of normal-sized azacycles (including Csp
8
α-lithiation of 1,2,3,4-tetrahydropyridine ), although simple N-
Boc aziridines undergo rapid N→C Boc migration following α-
As part of a program with the aim of providing flexible and
divergent routes to substituted 4-membered azacycles involving
substituent incorporation onto a pre-existing and straightfor-
wardly accessed azetidine core, we recently reported α4-
lithiation−electrophile trapping of N-thiopivaloylazetidine
9
lithiation. In the present case, we were pleased to find that the
10
known N-Boc-2-azetine (4) underwent regioselective lith-
2
11
iation at the α-sp position followed by deuteration to give 2-
D-2-azetine 6a (54% yield, 100% D, Scheme 2) under
5
and -azetidin-3-ol in enantio- and diastereocontrolled
Scheme 2. Lithiation−Deuteration of N-Boc-azetine (4)
processes, respectively. During the development of the latter
work, we found that the unprotected 3-hydroxyl group was
essential, as protection (e.g., as the TBS ether 2) only led to
efficient elimination on attempted α-lithiation−electrophile
trapping, to generate the corresponding stable 2-azetine 3
5
(
98%) (Scheme 1). This observation led us to consider the
possibility of α-electrophile incorporation using N-protected 2-
5
Scheme 1. Lithiation−Elimination of Silyloxythioamide 2
conditions typically used with N-Boc heterocycles [s-BuLi
1.2 equiv), TMEDA (1.2 equiv), THF, −78 °C, 1 h]. Further
experimentation established that n-BuLi was similarly effective
56%); the absence of TMEDA did not affect the yield (54%),
(
(
and LiTMP (1.4 equiv, THF, −78 °C, 45 min) also delivered
2
sp α-lithiation−trapping (70%).
Despite the above encouraging preliminary results, yield
variability in duplicate lithiation−deuteration experiments,
Received: December 16, 2013
©
XXXX American Chemical Society
A
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Organic Letters
Letter
1
3
Table 1. Scope of Carbonyl and Heteroatom Electrophiles
with Li-azetine 5
BuLi. The scope of the reaction with respect to electrophile
variation was investigated following these conditions (Table 1).
Aldehydes (Table 1, entries 2−5) and ketones (entries 6 and
7
), including an enal (entry 3) and potentially enolizable
substrates (entries 5 and 6), provided the corresponding
secondary and tertiary alcohols 6b−g in generally good yields.
Using carbonyl-based electrophiles at a higher oxidation level
(
BzCl, ethyl chloroformate, Mander’s reagent) or alkylating
agents (MeI, BuI, BnBr, allyl bromide) did not prove viable,
only resulting in the isolation of N-Boc azetine 4 or
decomposition of starting materials. However, heteroatom
incorporation could be achieved, generating the corresponding
silylated (entry 8), stannylated (entry 9), and halogenated 2-
azetines (entries 10−12), although in these latter cases
14
reversed-phase chromatography was necessary for satisfactory
product isolation.
Observations with two electrophiles (pivalaldehyde and
diphenyl disulfide) show further reactivity following electro-
phile trapping. While the hindered alcohol 6d derived from
pivalaldehyde could be isolated in good yield as indicated (84%,
Table 1, entry 4), exposure to CDCl which had not been
3
15
passed through alumina prior to use resulted in prototropy
driven by relief of strain, to the corresponding saturated ketone
(57%, Scheme 3); other aldehyde-derived adducts did not
8
undergo analogous isomerizations.
Scheme 3. Isomerization of Alcohol 6f to Ketone 8
Reaction with diphenyl disulfide (2.5 equiv) led, unusually, to
N-Boc-α-phenylthio-β-lactam (9) (40%, Scheme 4). The
Scheme 4. β-Lactam 9 from 3-Methoxyazetidine 7
a
1
Yield corrected for inseparable N-Boc-azetine 4 (10% by H NMR
12
analysis).
together with modest yields in the synthesis of N-Boc-azetine
4) [previously prepared (46%) by t-BuOK-induced elimi-
(
formation of β-lactam 9 may proceed through initial electro-
phile trapping where the resulting electron-rich azetine 6m
undergoes further reaction with the electrophile, followed by
hydrolysis (Scheme 4); reduction in the quantity of (PhS)2
used (to 0.9 or 1.0 equiv) did not result in recovery of any
identifiable products.
10
nation from the corresponding 3-tosylate; in our hands,
12
elimination (66%) by way of the 3-chloride was preferred ]
and the instability/tendency of unsubstituted N-Boc-azetine
(
−
4) to polymerize when left at rt and slowly during storage at
7
b,8
20 °C, led us to consider a modified strategy
where the
unsubstituted N-Boc-2-azetine (4) was generated and lithiated
in situ. This approach resulted in an efficient and reproducible
method to 2-D 6a (88% yield, 100% D) when N-Boc-3-
methoxyazetidine (7), available commercially or readily
While direct allylation of lithiated azetine 5 had proven
16
problematic, transmetalation to the organocopper allowed
C−C bond formation by nucleophilic substitution to give
allylated and propargylated azetines 10 (Table 2).
12
prepared by methylation (NaH, MeI, quant) of widely
Simple allylation and methallylation proceeded satisfactorily
(Table 2, entries 1 and 2). With unsymmetrical allylic bromides
available N-Boc-azetidin-3-ol, was reacted with 2.5 equiv of s-
B
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Organic Letters
Letter
Table 2. Scope of Copper-Mediated Allylation and
Propargylation
Scheme 6. Hydrogenation of a 2-Substituted Azetine
by way of transmetalation to copper, providing a direct entry to
-substituted N-Boc azetines. 2-Azetine stability depends
2
significantly on the electron-withdrawing ability of the N
substituent (aryl, sulfonyl, acyl, alkoxy carbonyl); our work
demonstrates that the comparatively modestly electron-with-
drawing Boc group is sufficient to allow isolation of 2-
substituted 2-azetines, provided they are handled, and in many
cases stored, under basic conditions. These studies indicate that
electrophile incorporation can be achieved on simple
monocyclic azetines and suggest that further opportunities
exist for azetine diversity generation using this strategy, with
potential to access substituted azetidines through double bond
manipulation.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Full experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: david.hodgson@chem.ox.ac.uk.
Notes
a
Isolated ratio after chromatography.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(
cinnamyl, crotyl, and prenyl), mixtures of S 2- and S 2′-
■
N
N
1
derived azetines were observed [S 2:S 2′ by crude H NMR
We thank AstraZeneca and the EPSRC for studentship support
(to C.I.P.) and the Higher Education Commission of Pakistan
for an IRSIP scholarship (to M.K.).
N
N
analysis, 91:9 (entry 3), 47:53 (entry 4), 66:33 (entry 5)], while
propargylation proceeded by S 2 (entries 6 and 7). The latter
N
contrasts with S 2′ regioselectivity giving allenes seen with N-
N
17
REFERENCES
Boc-α-aminoalkylcuprates.
■
While attempted Suzuki cross-couplings with bromide 6k did
(1) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108,
3988−4035.
2) (a) Moore, J. A.; Ayers, R. S. In Chemistry of Heterocyclic
18,19
not prove viable, Negishi coupling
gave 2-phenylated
(
azetine 11 in 27% yield (Scheme 5).
Compounds: Small Ring Heterocycles - Part 2; Hassner, A., Ed.; Wiley:
New York, 1983; Part 2, pp 1−217. (b) Jubault, P.; Leclerc, E.;
Quirion, J.-C. In Science of Synthesis; Molander, G. A., Ed.; Thieme:
Stuttgart, 2006; Vol. 33, pp 577−582.
3) For recent studies, see: (a) Mangelinckx, S.; Van Speybroeck, V.;
Vansteenkiste, P.; Waroquier, M.; De Kimpe, N. J. Org. Chem. 2008,
3, 5481−5488. (b) Barluenga, J.; Riesgo, L.; Lonzi, G.; Tomas, M.;
Lop
ez, L. A. Chem.Eur. J. 2012, 18, 9221−9224.
4) Hodgson, D. M.; Kloesges, J. Angew. Chem., Int. Ed. 2010, 49,
Scheme 5. Phenylated Azetine 11 by Negishi Cross-Coupling
(
7
́
́
(
2
900−2903.
3
b
Hydrogenation of a carbonyl-derived azetinol 6f provided
straightforward access to the corresponding saturated azetidine
alcohol 12 (86%, Scheme 6); as noted previously, such adducts
are not available by α-lithiation−electrophile trapping of N-
Boc-azetidine, although N-thiopivaloylazetidine is a viable
(5) Hodgson, D. M.; Pearson, C. I.; Thompson, A. L. J. Org. Chem.
2013, 78, 1098−1106.
(6) Chromatographic purification of these substituted thioamide
azetines proved challenging, usually resulting in significant loss of
material, and with products typically eluting with nonpolar byproducts.
(7) (a) Beak, P.; Lee, W.-L. Tetrahedron Lett. 1989, 30, 1197−1200.
b) Beak, P.; Lee, W. L. J. Org. Chem. 1993, 58, 1109−1117.
c) Gawley, R. E.; O’Connor, S.; Klein, R. In Science of Synthesis;
4
substrate.
(
(
In summary, commercially available N-Boc-3-methoxyazeti-
dine (7) has been shown to undergo α-lithiation−elimination
to form N-Boc-azetine (4) in situ, which can be further α-
Snieckus, V., Majewski, M., Eds.; Thieme: Stuttgart, 2006; Vol. 8a, pp
6
77−757.
2
8,11
lithiated regioselectively at the sp center and trapped with a
range of electrophiles, including allylic and propargylic halides
(8) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155−
158.
C
dx.doi.org/10.1021/ol403626k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
9) (a) Capriati, V.; Florio, S.; Luisi, R.; Musio, B. Org. Lett. 2005, 7,
3
749−3752. (b) Hodgson, D. M.; Humphreys, P. G.; Xu, Z.; Ward, J.
G. Angew. Chem., Int. Ed. 2007, 46, 2245−2248. (c) Hodgson, D. M.;
Humphreys, P. G.; Miles, S. M.; Brierley, C. A. J.; Ward, J. G. J. Org.
Chem. 2007, 72, 10009−10021.
(
10) McDonald, R. I.; Wong, G. W.; Neupane, R. P.; Stahl, S. S.;
Landis, C. R. J. Am. Chem. Soc. 2010, 132, 14027−14029.
11) (a) Tae, J.; Paquette, L. A. Can. J. Chem. 2000, 78, 689−696.
b) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342−
344.
(
(
5
(
12) See the Supporting Information for details.
(
13) s-BuLi without TMEDA gave 2-D-2-azetine 6a (74% 100% D).
LiTMP (2.5 equiv, THF −78 °C) gave 2-D-2-azetine 6a (62%, 100%
D) after 5 h (48%, 100% D after 30 min).
(
(
14) Farina, V. J. Org. Chem. 1991, 56, 4985−4987.
15) Green, M. B.; Hickinbottom, W. J. J. Chem. Soc. 1957, 3270−
3274.
(
16) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu,
K.; Watson, R. T. J. Org. Chem. 2004, 69, 3076−3086.
(
(
17) Coldham, I.; Leonori, D. J. Org. Chem. 2010, 75, 4069−4077.
18) (a) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C. J. Am. Chem. Soc. 2006, 128, 3538−3539. (b) Barker, G.;
O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176−4179. (c) Barker,
G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.;
O’Brien, P. J. Org. Chem. 2011, 76, 5936−5953.
(
19) No 2-phenylated azetine 11 was isolated if TMEDA was
present; see also ref 18c.
D
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