Lithiation-electrophilic substitution of N-thiopivaloylazetidine

Article abstract of DOI:10.1002/anie.201000058

(Figure Presented) The fourth protocol: The rarely studied Nthiopivaloyl group plays a crucial role in mediating efficient ∞ lithiation and incorporation of diverse electrophiles onto an azetidine ring; in the presence of chiral ligands, this chemistry also provides the first example of an enantioselective electrophilic substitution on a four-membered ring.

Full text of DOI:10.1002/anie.201000058

Communications
DOI: 10.1002/anie.201000058
Heterocycles
Lithiation–Electrophilic Substitution of N-Thiopivaloylazetidine**
David M. Hodgson* and Johannes Kloesges
Owing to the widespread importance of amines, advances in
their synthesis and elaboration continue to constitute a major
area of chemical research.[1] The main strategies that have
been employed for the convergent assembly of a-branched
phile-trapping at the position a to the nitrogen atom,[2] to the
best of our knowledge there are only two isolated examples of
trapping on an azetidine ring: the reaction of N-nitroso-
azetidine (1, PG = NO) with LDA (LDA = lithium diiso-
propylamide; THF, À788C), followed by addition of benzo-
phenone gave the corresponding tertiary alcohol (65%
yield),[7] and the reaction of N-(triphenylacetyl)azetidine (1,
PG = COCPh3) with tBuLi (THF, À408C) and benzaldehyde
gave the corresponding secondary alcohol (62% yield, d.r. not
reported).[8] However, we decided against examining these
azetidines in more detail owing to several drawbacks with
both methods; carcinogenicity and poor prospects for asym-
metric induction were concerns with the former, whilst
disadvantages of the latter included the use of a high
molecular weight triphenylacetyl group and the requirement
of tBuLi to achieve the metalation, which was considered
problematic for the later development of an asymmetric
variant of the reaction.[9] Furthermore, complications have
been observed from ortho-lithiation at the triphenylacetyl
group followed by a carbamoyl group 1,3-shift,[8] and in our
hands the reported metalation proved problematic.
À
amines are reductive amination, alkene hydroamination, C
H insertion by a nitrogen source, carbanion addition to
À
imines, and the reaction of an a-C H bond of a suitably N-
protected/activated amine. Whilst several ways exist to
achieve the latter strategy with saturated azacycles of various
ring size,[2] there is currently no general method of achieving
this with an azetidine (1) to give a 2-substituted azetidine (2,
PG = protecting/activating group; Scheme 1), particularly in
an enantioselective manner. Substituted azetidines are often
challenging to synthesize but have significance and current
interest as bioactive entities; they have also been used as
ligands in metal-catalyzed transformations and as chiral
auxiliaries.[3] Herein, we report a promising route to 2-
substituted azetidines from azetidine itself, the latter being
readily available in multi-kilogram quantities.[4]
Initially, we investigated N-Boc-azetidine (1, PG =
Boc)[10] because of the likelihood of facile deprotonation, by
analogy to its higher[11] and lower ring-size homologues.[12]
However, N-Boc-azetidine (1, PG = Boc) was found to be
inert to lithium amides (LDA or LTMP, LTMP = lithium
2,2,6,6-tetramethylpiperidide) that had previously been used
to lithiate related aziridines. The use of sBuLi was also
unsatisfactory; no reaction or partial lithiation (36% [D]
incorporation by GC-MS using CD3OD as the electrophile)
was seen after 25 minutes at À788C in diethyl ether or
tetrahydrofuran, respectively, and attempts to induce greater
conversion in either solvent by warming or by adding
tetramethylethylenediamine (TMEDA) as an additive only
led to complex mixtures of products (including for the latter
case in tetrahydrofuran, significant attack on the carbamoyl
group).[13] In contrast to the corresponding aziridine,[14] N-
sulfinylazetidine (1, PG = SOtBu) mainly underwent decom-
position with lithium amide or organolithium reagents,
whereas N-tert-butylsulfonyl- and N-(diethylphosphonyl)aze-
tidines (1, PG = SO2tBu and PO(OEt)2, respectively) resisted
lithiation under a variety of conditions. At this stage, a review
of the less commonly used N-protecting/activating groups for
deprotonation at the position a to the nitrogen atom[2] led us
to consider the thiopivaloyl group, even though the literature
was not encouraging: Seebach and Lubosch originally
reported that out of several secondary amine-derived thio-
pivalamides studied (including that from piperidine), only the
thiopivalamide that was derived from dimethylamine could
be lithiated (sBuLi/TMEDA, THF, À788C) and trapped with
electrophiles.[15] To examine this chemistry with azetidine (3),
the derived crude pivalamide was treated with P2S5 to give
À
Scheme 1. Substitution at the C2 position of N PG azetidine 1.
PG=protecting/activating group.
There are few previous studies concerning the reaction of
the a-C H bonds of N-substituted azetidine. The two-step
introduction of some nucleophiles at the C2-position of N-
À
tosylazetidine (1, PG = Ts) has been achieved using anodic C2
acetoxylation,[5] whilst the attempted direct C H insertion of
À
N-Boc-azetidine (1, PG = Boc) using methyl phenyldi-
azoacetate under RhII catalysis formed a complex mixture
of products (normal-sized azacycles were much more effec-
tive).[6] Within the large body of work on metalation–electro-
[*] Prof. D. M. Hodgson, J. Kloesges
Department of Chemistry, Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
Fax: (+44)1865-285002
E-mail: david.hodgson@chem.ox.ac.uk
Homepage: http://hodgson.chem.ox.ac.uk
[**] We thank the EPSRC (DTA) and GlaxoSmithKline for financial
support for this work. We also thank the EPSRC National Mass
Spectrometry Service Centre (Swansea) for mass spectra, Dr. A.
Thompson (Oxford) for X-ray crystallographic analysis, Dr. C. J. R.
Bataille (Oxford) for chiral GC analyses, and Dr. D. T. Tape
(GlaxoSmithKline) for useful discussions.
Supporting information for this article, including experimental
procedures, is available on the WWW under http://dx.doi.org/10.
1002/anie.201000058.
2900
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 2900 –2903

Angewandte
Chemie
Table 1: Scope of electrophile incorporation into thioamide 4.
thioamide 4 following simple distillation (83% from 3,
Scheme 2). Remarkably, and in stark contrast to our obser-
vations with the other azetidines discussed above, thioamide 4
underwent very clean lithiation–deuteration, to give 2-deu-
terated azetidine 5a in excellent yield (Scheme 2). The
importance of the thioamide functionality to the success of
this transformation was underlined when a lithiation of the
precursor pivalamide was attempted: only 2,2,4-trimethyl-
hexan-3-one, which arises from the attack of sBuLi at the
amide carbonyl carbon atom, was observed (LTMP returned
only the starting pivalamide).
Entry
Electrophile
Substituted azetdine
Yield [%]
91
1
Me3SiCl
5b
5c
2
3
Me3SnCl
PhCHO
86
5d
87[a]
4
5
p-ClC6H4CHO
5e
5 f
68[b]
(CH3)2CO
94
Scheme 2. Preparation, lithiation, and deuteration of thioamide 4.
py=pyridine, DMAP=4-dimethylaminopyridine, Piv=pivaloyl.
6
7
CO2
MeI
5g
5h
61[c]
93
Next, the scope of electrophile incorporation into thio-
amide 4 was investigated (Table 1). Silylation and stannyla-
tion were equally viable (Table 1, entries 1 and 2), as were
reactions using carbonyl-based electrophiles (Table 1,
entries 3–6); the excellent yield found with acetone (94%;
Table 1, entry 5) indicates that potentially competing enoli-
zation is not a problem. For entries 3 and 4, single diastereo-
mers were observed; the product in entry 3 was established by
X-ray crystallographic analysis to have an R*,R* configura-
tion (see the Supporting Information). This excellent diaste-
reoselectivity is noteworthy, given the absence of such
selectivity when using aldehydes with a-lithiated aziridines,[14]
N-Boc-pyrrolidine, or N-Boc-piperidines.[11] Alkylation of
dipole-stabilized organolithium compounds using alkyl hal-
ides can be inefficient (ascribed to the intervention of single-
electron transfer processes),[2b,11] but thioamide 4 was found
to undergo methylation, allylation, benzylation, and butyla-
tion in uniformly high yields (79–93%, entries 7–10). Using
MeLi, we also established the viability of removing the
thiopivaloyl group from an a-substituted azetidine (81%
from 5i, isolated as the hydrochloride salt; conversion into the
corresponding pivalamide, in 93% yield from 5i, was also
achieved with CH3CO3H).[15]
8
BnBr
5i
81
9
CH2CHCH2Br
BuBr
5j
79
83
10
5k
[a] Isolated as a single diastereomer (R*,R*). [b] Stereochemistry
assigned by analogy to 5d. [c] Isolated as the methyl ester following
reaction with TMSCHN2.
Possible extension of this procedure to incorporate
electrophiles onto the protected aziridine in an enantiocon-
trolled fashion was first examined by replacing TMEDA with
the lupine alkaloid (À)-sparteine (6; Scheme 3); this chiral
ligand has previously been shown to be effective in several
asymmetric lithiation reactions.[9,16,17] When methyl iodide
was used as the electrophile in diethyl ether, methylated
azetidine (R)-5h was obtained in an e.r. of 61:39 (99%
conversion by GC-MS; Table 2, entry 1).[18] The stereochem-
istry of the major enantiomer was established by comparison
with material synthesized from commercial N-Boc-(S)-azeti-
dine-2-carboxylic acid (see the Supporting Information), and
Scheme 3. Ligands examined in the asymmetric lithiation and
methylation of thioamide 4.
Angew. Chem. Int. Ed. 2010, 49, 2900 –2903
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2901

Communications
Table 2: Effect of ligand and solvent on asymmetric lithiation and
methylation of thioamide 4.
studied N-Boc-pyrrolidine system. Furthermore, subsequent
high-yielding removal of the N-thiopivaloyl group has been
demonstrated. To the best of our knowledge, this chemistry
also provides the first example of enantioselective electro-
philic substitution on a four-membered ring.[25] It is tempting
to speculate that, as with the N-Boc-pyrrolidine and piper-
idine systems,[2b] a ternary pre-lithiation complex involving
the azetidine, organolithium and (chiral) ligand species
facilitates the proton removal (equatorial, from a puckered
azetidine conformation) to give a configurationally stable
dipole-stabilized a-lithiated azetidine that undergoes meth-
ylation with retention of stereochemistry (SE2ret). However,
reversal of the major enantiomer compared with these other
systems means that such speculation must be treated with
caution at this stage and awaits clarification through mech-
anistic studies. Nevertheless, the promising levels of asym-
metric induction, which were obtained using a ligand that is
commercially available as either enantiomer and which has
scope for structural variation (unlike sparteine), suggests this
and related systems will provide fertile ground for future
investigations.
Entry[a]
Ligand
Solvent
e.r. 5h R:S
Conversion [5h/4][b]
1
2
3
6
6
6
6
6
6
6
7
7
8
8
9
9
9
9
Et2O
TBME
THF
hexane
hexane
hexane
pentane
hexane
Et2O
hexane
Et2O
hexane
Et2O
61:39
59:41
54:46
72:28
52:48
60:40
71:29
46:54
–
47:53
37:63
62:38
80:20
78:22
76:24
99:1
99:1
99:1
99:1
99:1
99:1
97[f]
97:3
0:100
95:5
78:22
99:1
96[f]
4
5[c]
6[d]
7[e]
8
9
10
11
12
13
14[e]
15
Et2O
TMBE
99:1
99:1
[a] sBuLi (1.2 equiv), ligand (1.2 equiv), unless otherwise indicated.
[b] by GC-MS, unless otherwise indicated. [c] 2.5 equivalents of 6 used.
[d] sBuLi (4 equiv), 6 (4 equiv). [e] À1008C. [f] Yield of isolated 5h.
Received: January 6, 2010
Published online: March 16, 2010
was found to be opposite to that previously observed with
sBuLi/6 using N-Boc-pyrrolidine as the substrate.[17] A study
of the effect of solvent on the enantiomeric ratio found little
change when tert-butyl methyl ether was used, a slight
lowering in tetrahydrofuran, and an improvement to 72:28
in hexane (Table 2, entries 2–4). In hexane, increasing the
proportion of (À)-sparteine (6) relative to sBuLi, or the
number of equivalents of sBuLi/6, led to lower enantiomeric
ratios (Table 2, entries 5 and 6), whereas conducting the
reaction at À1008C (in pentane) led to a similar result (5h
isolated in 97% yield) to that initially observed in hexane
(Table 2, entry 7). Proline-based ligands 7 and 8 were less
effective than sparteine (Table 2, entries 8–11).[19] Alexakis
and co-workers originally introduced trans-cyclohexane-1,2-
diamines, such as 9 (now commercially available),[20] as
ligands for the enantioselective addition of methyllithium to
imines, in which the different substituents on each nitrogen
atom allowed both heteroatoms to become stereocenters
when chelated to the metal;[21] more recently, this diamine has
been shown to induce asymmetric a lithiation of N-Boc-
pyrrolidine with high efficiency, comparable to that obtained
with (À)-sparteine (6).[22] When thioamide 4 was used as the
substrate, although ligand 9 (in hexane) gave a lower e.r. value
(Table 2, entry 12) compared to (À)-sparteine (6) (Table 2,
entry 4), ligand 9 was found to be superior in ethereal solvents
(up to 80:20 e.r. in diethyl ether at À788C, 96% yield of 5h;
Table 2, entries 13–15).
Keywords: asymmetric synthesis · azetidines ·
.
electrophilic substitution · lithiation · synthetic methods
[1] a) S. A. Lawrence, Amines: Synthesis Properties and Applica-
tions, Cambridge University Press, Cambridge, 2004; b) “Amines
and Ammonium Salts”: Science of Synthesis, Vol. 40a (Eds.: E.
Schaumann, D. Enders), Thieme, Stuttgart, 2009.
[2] a) P. Beak, W. J. Zajdel, D. B. Reitz, Chem. Rev. 1984, 84, 471 –
523; b) R. E. Gawley, S. OꢀConnor, R. Klein in Science of
Synthesis, Vol. 8a (Eds.: V. Snieckus, M. Majewski), Thieme,
Stuttgart, 2006, pp. 677 – 757; c) Asymmetric Synthesis of Nitro-
gen Heterocycles (Ed.: J. Royer), Wiley-VCH, Weinheim, 2009.
[3] a) G. S. Singh, M. D’Hooghe, N. De Kimpe in Comprehensive
Heterocyclic Chemistry III, Vol. 2 (Ed.: C. V. Stevens), Elsevier,
Oxford, 2008, pp. 1 – 110; b) A. Brandi, S. Cicchi, F. M. Cordero,
Chem. Rev. 2008, 108, 3988 – 4035; c) F. Couty in Science of
Synthesis, Vol. 40a (Eds.: E. Schaumann, D. Enders), Thieme,
Stuttgart, 2009, pp. 773 – 816.
[4] D. H. Causey, R. P. Mays, D. A. Shamblee, Y. S. Lo, Synth.
Commun. 1988, 18, 205 – 211.
[5] T. Shono, Y. Matsumura, K. Uchida, F. Nakatani, Bull. Chem.
Soc. Jpn. 1988, 61, 3029 – 3031.
[6] H. M. L. Davies, C. Venkataramani, T. Hansen, D. W. Hopper, J.
Am. Chem. Soc. 2003, 125, 6462 – 6468.
[7] D. Seebach, D. Enders, B. Renger, Chem. Ber. 1977, 110, 1852 –
1865.
In summary, we report a method for the a incorporation
of electrophiles onto azetidine, in which the rarely studied N-
thiopivaloyl group[15,23] plays a crucial role. The origins of its
effectiveness (compared with the more typical N-activating
substituents examined above) are not known, but may result
from a combination of a-position activation and a reduced/
absent propensity for attack of the base at the thiocarbonyl
functionality.[24] This method tolerates a variety of different
electrophiles, and affords products in good diastereoselectiv-
ities; indeed, the scope is arguably better than for the well-
[8] W. Wykypiel, J.-J. Lohmann, D. Seebach, Helv. Chim. Acta 1981,
64, 1337 – 1346.
[9] Organolithiums in Enantioselective Synthesis: Topics in Organ-
ometallic Chemistry, Vol. 5 (Ed.: D. M. Hodgson), Springer,
Berlin, 2003.
[10] D. Chang, H.-J. Feiten, K.-H. Engesser, J. B. van Beilen, B.
Witholt, Z. Li, Org. Lett. 2002, 4, 1859 – 1862.
[11] P. Beak, W. K. Lee, J. Org. Chem. 1993, 58, 1109 – 1117.
[12] a) D. M. Hodgson, P. G. Humphreys, Z. Xu, J. G. Ward, Angew.
Chem. 2007, 119, 2295 – 2298; Angew. Chem. Int. Ed. 2007, 46,
2245 – 2248; b) D. M. Hodgson, P. G. Humphreys, S. M. Miles,
2902 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 2900 –2903

Angewandte
Chemie
C. A. J. Brierley, J. G. Ward, J. Org. Chem. 2007, 72, 10009 –
10021.
[13] W. F. Bailey, P. Beak, S. T. Kerrick, S. Ma, K. B. Wiberg, J. Am.
Chem. Soc. 2002, 124, 1889 – 1896.
[14] D. M. Hodgson, S. P. Hughes, A. L. Thompson, T. D. Heightman,
Org. Lett. 2008, 10, 3453 – 3456.
[15] a) D. Seebach, W. Lubosch, Angew. Chem. 1976, 88, 339 – 340;
Angew. Chem. Int. Ed. Engl. 1976, 15, 313 – 314; b) W. Lubosch,
D. Seebach, Helv. Chim. Acta 1980, 63, 102 – 116.
[16] D. Hoppe, Synthesis 2009, 43 – 55.
[17] P. Beak, S. T. Kerrick, S. Wu, J. Chu, J. Am. Chem. Soc. 1994, 116,
3231 – 3239.
[18] Other electrophiles are under investigation.
[19] I. Coldham, P. OꢀBrien, J. J. Patel, S. Raimbault, A. J. Sanderson,
D. Stead, D. T. E. Whittaker, Tetrahedron: Asymmetry 2007, 18,
2113 – 2119.
[20] Both enantiomers of diamine 9 are available from TCI.
[21] J.-C. Kizirian, J.-C. Caille, A. Alexakis, Tetrahedron Lett. 2003,
44, 8893 – 8895.
[22] D. Stead, P. OꢀBrien, A. Sanderson, Org. Lett. 2008, 10, 1409 –
1412.
[23] For a recent review on thioamides, see: J. Moore in Compre-
hensive Organic Functional Group Transformations II, Vol. 5
(Eds.: A. R. Katritzky, R. J. K. Taylor), Elsevier, Amsterdam,
2005, pp. 519 – 570.
[24] K. B. Wiberg, P. R. Rablen, J. Am. Chem. Soc. 1995, 117, 2201 –
2209.
[25] For enantioselective deprotonation–enol silane formation from
3-substituted cyclobutanones, see: E. Lee-Ruff, G. Mladenova,
Chem. Rev. 2003, 103, 1449 – 1483.
Angew. Chem. Int. Ed. 2010, 49, 2900 –2903
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2903