Pseudoephedrine-Directed Asymmetric α-Arylation of α-Amino Acid Derivatives

Article abstract of DOI:10.1002/anie.201502569

Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.

Full text of DOI:10.1002/anie.201502569

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502569
German Edition: DOI: 10.1002/ange.201502569
Chiral Auxiliaries
Pseudoephedrine-Directed Asymmetric a-Arylation of a-Amino Acid
Derivatives**
Rachel C. Atkinson, Fernando Fernµndez-Nieto, Josep Mas Roselló, and Jonathan Clayden*
Abstract: Available a-amino acids undergo arylation at their
a position in an enantioselective manner on treatment with
base of N’-aryl urea derivatives ligated to pseudoephedrine as
a chiral auxiliary. In situ silylation and enolization induces
diastereoselective migration of the N’-aryl group to the
a position of the amino acid, followed by ring closure to
a hydantoin with concomitant explulsion of the recyclable
auxiliary. The hydrolysis of the hydantoin products provides
derivatives of quaternary amino acids. The arylation avoids the
use of heavy-metal additives, and is successful with a range of
amino acids and with aryl rings of varying electronic character.
enolates with migration of an aromatic ring from N to C. The
reaction formally involves an intramolecular nucleophilic
aromatic substitution reaction,[31,32] but is much more general
with regard to ring electronics than a typical SNAr reaction.[33]
Kawabata et al.[34] simultaneously reported a chiral memory
effect in a related reaction that allowed certain members of
the class of a-aryl a-amino acid derivatives to be prepared
with good enantioselectivity.
Aiming to solve the problem of asymmetric arylation of
amino acids, particularly with electron-rich rings, we decided
to start from Myersꢀ very general methods for asymmetric
alkylation,[8,9,35,36] with the goal of developing an intramolec-
ular asymmetric a-arylation of amino acids employing (S,S)-
pseudoephedrine (2) as an auxiliary (Scheme 1). Coupling 2
to the urea derivative 1 of N-methyl-l-Ala yielded the alanine
amide 3, typically as a 4:1–5:1 mixture of diastereoisomers.
T
he central role of amino acids in nature makes them one of
the most important targets for modification in medicinal
chemistry and chemical biology.[1] One modification in
particular, the stereoselective functionalization of the a-
carbon atom to prepare quaternary a-amino acids and their
derivatives, has led to compounds of major structural and
medicinal significance.[2]
A range of methods for the asymmetric a-alkylation of
readily available amino acids makes simple quaternary amino
acids bearing a-alkyl groups readily accessible.[3–9] There are
far fewer options for the asymmetric introduction of aryl
rings[10,11] to the a-carbon atom of a-amino acids to make
quaternary a-arylated amino acids, and those that exist suffer
from severe limitations in scope. Racemic a-arylations have
been achieved through Pd[12–14] or Fe[15] catalyzed reactions of
enolates to form heterocyclic amino acid derivatives, with an
asymmetric version requiring
a
complex multi-step
sequence.[16] Electron-deficient rings may be introduced
intra-[17–20] or intermolecularly[21–23] by stereoselective aryne
or SNAr chemistry. Maruoka et al.[24] achieved an asymmetric
phase-transfer arylation with Cr complexes of electron-rich
arenes.
Scheme 1. Enantioselective arylation of an amino acid derivative.
The results of forming the enolate 4 by treatment of 3 with
an excess (> 2 equiv) of base are shown in Table 1. A change
in the ratio of diastereoisomers of the starting material
provided evidence that deprotonation by alkyllithium
reagents gave an enolate at temperatures above À788C
(Table 1, entry 1), and fast warming of the enolate to room
temperature gave the hydantoin 6 as its S enantiomer with
moderate enantiomeric enrichment (Table 1, entries 1 and 2;
see below for stereochemical determination). Presumably, the
enolate 4 rearranges to 5 with migration of the phenyl ring to
the a-carbon atom of the alanine residue, and the hydantoin 6
is formed by ring closure with expulsion of the auxiliary 2.
HMDS bases gave poorer yields and selectivity (Table 1,
entries 4–6), but selectivity was markedly improved in the
presence of LiCl (entries 7–9), a result consistent with the
work of Myers et al.[35] Yields were highest when lithium
amide bases (LDA or LiTMP) were used. Under optimum
We previously reported[25] a racemic approach to the
synthesis of a-aryl amino acids that makes use of the
rearrangement of N-aryl urea derivatives[26–30] of amino acid
[*] R. C. Atkinson, Dr. F. Fernµndez-Nieto, J. Mas Roselló,
Prof. J. Clayden
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: clayden@man.ac.uk
[**] This work was funded by the EPSRC (studentships to R.C.A. and
J.M.R.), the Xunta de Galicia (plan I2C, fellowship to F.F.N.), and
Syngenta (CASE award to J.M.R.). We thank Dr. Simon Hardy
(Syngenta) for valuable discussions and Mary Okoh for synthetic
assistance. Jonathan Clayden is the recipient of a Royal Society
Wolfson Research Merit Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502569.
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Table 1: Rearrangement of alanine derivative 3 to hydantoin (S)-6.
Table 2: Rearrangement of unsubstituted amino acid derivatives 7a,b to
hydantoins 9a,b.
Entry
Base (equiv)
Additive (equiv)
Yield
of 6 [%]
e.r. of 6
(R:S)
Entry SM Base
(equiv)
equiv of equiv of (R)-9,
LiCl
e.r. of 9
Me3SiCl Yield[a] [%] (R:S)
1
sBuLi (3)
DMPU (20)
0,[a]
47[b]
68
56
41
–,[a,c]
22:78[b]
22:78
23:77
60:40
39:61
32:68
8:92
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
LDA (4)
LiTMP (4)
LDA (4)
LDA (4)
LDA (4)
7
7
7
7
7
-
7
7
7
0
7
0
7
–
0
0
9a, 54
9a, 43
9a, 60
9a, 65[b]
0
50:50
55:45
75:25
92:8
–
–
86:14
–
10:90
79:21
91:9
–
2
3
4
5
6
7
8
nBuLi (3)
LDA (3)
–
–
–
–
1
KHMDS (3)
NaHMDS (3)
LiHMDS (3)
nBuLi (4.5)
LDA (3)
2[b]
[c]
50
44
49
3 or 4
2
1
2
2
2
2
1
–
KHMDS (4)
0
LiCl (12)
LiCl (12)
10a LDA (3)
10a LDA (3)
10b LDA (4)
10c LDA (4)
10d LDA (4)
10e LDA (4)
9a, 50[d]
0
66,[d]
72[e]
64
10:90,[d]
12:88[e]
8:92
9
9a, 68
9a, 82[e]
9a, 32
0
9
LiTMP (3)
LiCl (12)
10
11
12
13
14
General conditions: À78!+208C in THF (0.1m). [a] À788C for 7 h,
slow warming to +208C. [b] À788C for 0.5 h, rapid warming to +208C.
[c] Recovered 3 had d.r. of 85:15 at À788C and of 70:30 at RT.
[d] 0.1 mmol. [e] 0.32 mmol.
7b
7b
LDA (4)
2
2.1
9b, 24
92:8
93:7
LDA (2+2)[f]
9b, 70[g]
[a] After quenching with HCl, except entry 14. [b] Slightly lower yield and
e.r. obtained with Me3SiOTf; with TBDMSOTf or TBDMSCl the reaction
failed to reach completion and gave lower e.r. [c] Starting material (SM)
recovered (accompanied by an epimer when 4 equiv Me3SiCl were used).
[d] Yield determined by NMR spectroscopy. [e] Yield of crude product.
[f] LDA (2 equiv) was added to the substrate, followed by Me3SiCl
(2.1 equiv). After 30 min, a further 2 equiv of LDA were added, and after
15 min, the mixture was warmed to room temperature. [g] After
quenching with K2CO3 in MeOH.
conditions, the hydantoin 6 was obtained in about 70% yield
and 90:10 e.r.
The doubly N-methylated hydantoin product 6 proved
extremely resistant to hydrolysis[25] to the corresponding
quaternary N-methylated amino acid, so we modified the
substrates 3 with the aim of rearranging their N-unsubstituted
analogues 7 (Scheme 2). These were conveniently obtained as
single diastereoisomers by acylating l-AlaOEt or l-MetOMe
with N-phenyl-N-methyl carbamoyl chloride, ester hydrolysis,
and coupling the resulting urea with (S,S)-pseudoephedrine
(2).
Treatment of 7a with four equivalents of LDA or LiTMP
in the presence of LiCl gave the corresponding hydantoin 9a
in moderate yield, but as a racemic mixture (Table 2, entries 1
and 2). Reasoning that N substitution may be essential for
stereoselective rearrangements, we added trimethylsilyl chlo-
ride to the reaction mixture with the aim of trapping the
anionic urea in situ, yet still allowing enolate 8C to form and
the rearrangement to take place. With one equivalent of
Me3SiCl, some enantiomeric enrichment was observed
(Table 2, entry 3), but with two equivalents of Me3SiCl, the
e.r. of product 9a rose to 92:8 in favor of the R enantiomer
(entry 4). The yield of 65% represents the outcome of
a multi-step sequence of deprotonation, silylation, rearrange-
ment, cyclization, and desilylation. Three equivalents or more
of Me3SiCl lowered the yield and led to the recovered starting
material as a mixture of epimers (Table 2, entry 5). A screen
of other silylating agents resulted in none that performed
better than Me3SiCl (Table 2, entry 4), and the use of
KHMDS gave no product (entry 6).
This dependence of the reaction on the number of
equivalents of silylating agent is very informative. As maximal
yields and enantiomeric ratios were obtained with two
equivalents of Me3SiCl, we propose that this stoichiometry
allows silylation firstly of the pseudoephedrine hydroxy group
and secondly of the urea anion (probably[37] on the oxygen
atom), giving a doubly silylated intermediate whose depro-
tonation results in an enolate 8C capable of selective
rearrangement. Less than two equivalents of silylating agent
gave lower enantioselectivity, possibly because the corre-
sponding unsilylated species 8A and/or monosilylated species
8B may still lead to competing rearrangement, but without
selectivity.[38] We assume that more than two equivalents of
Me3SiCl leads to an unreactive silyl enol ether 8D, whose
hydrolysis at work up can therefore return partly epimerized
starting material (Table 2, entry 5). Support for this explan-
ation of the need for two equivalents of Me3SiCl was provided
by rearrangement of the alternative starting material 10a, in
Scheme 2. Optimization of the enantioselective rearrangement.
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which preliminary silylation of the pseudoephedrine auxiliary
gave a good e.r. even with one equivalent of Me3SiCl (Table 2,
entry 7), but returned starting material with two equivalents
of Me3SiCl (entry 8).
The other enantiomer of the pseudoephedrine auxiliary
gave the epimeric starting material 10b, which rearranged to
(S)-9a with no evident match/mismatch effects (Table 2,
entry 9).[9,36] Alternative auxiliaries performed less well:
ephedrine (10c) gave poorer selectivity (Table 2, entry 10);
pseudephenamine[39,40] (10d) gave lower yields (entry 11)
possibly because of competing benzylic deprotonation[27] a to
the N atom, and Evansꢀ oxazolidinone derivative 10e was
unstable to the reaction conditions (entry 12).
Extension of the optimal conditions summarized in
entry 4 of Table 2 for the arylation of alanine to the
methionine-derived substrate 7b gave hydantoin products in
equally good enantiomeric ratios, but significantly lower yield
(entry 13). The reaction protocol was therefore modified
(Table 2, entry 14) to ensure that both the hydroxy group of
pseudoephedrine and the N atom of urea were fully silylated
before formation of the enolate 8C. As this reaction no longer
takes place through an alkoxide intermediate, we also omitted
LiCl[35] from the reaction mixture. As a consequence, the yield
of the hydantoin (R)-9b increased to 70% and the stereose-
lectivity to 93:7 e.r.
These optimized conditions were applied to a range of
substrates (7a–v, Scheme 3). Each starting material was
prepared in three steps from the methyl or ethyl ester of the
corresponding amino acid. Acylation with the appropriate
carbamoyl chloride[41] was followed by ester hydrolysis and
coupling with pseudoephedrine to give the ureas 7, which
were treated with LDA and Me3SiCl.
The domino process of silylation, enolization, arylation,
and cyclization to give hydantoin derivatives of alanine,
methionine, butyrine, n-propylglycine, leucine, lysine, and
proline with a phenyl ring (9a–g) or other electron-rich (9i–l)
rings proceeded with moderate to good yields, and with high
levels of stereoselectivity. Crystallization from chloroform
returned (Æ)-9a as a racemate[42] and evaporation of the
mother liquor gave (R)-9a with the enantiomeric ratio
enhanced to 99:1. Rearrangement of the more hindered
leucine was less clean (and all attempted rearrangements of
valine- or phenylglycine-derived ureas failed), suggesting that
leucine lies at the limit of the methodꢀs tolerance to steric
hindrance. Arylation with more electron-deficient rings (9m–
s), and arylation of pipecolic acid (9h), gave slightly to
substantially lower enantioselectivities, and in some cases low
yields, even when the non-stereoselective arylations from 11
or 12 were clean reactions. Some substrates (generally those
with acidic protons in the b position, 7t–v) failed to rearrange
cleanly,[43] although the racemic products 9t–v were formed in
good yield from 11 or 12.
Scheme 3. Asymmetric arylation of a range of amino acids. Yields and
enantiomeric ratios quoted for hydantoin products 9. [a] (Æ)-Amino
ester used for 7c,d,h,j,t (which are therefore a diastereoisomeric
mixture). [b] LDA used for the racemic rearrangement of 12 to
9a–c,e,k,u. [c] Representative recovery of pure (S,S)-pseudoephedrine
from the rearrangement of 9a. [d] Racemic product obtained from the
rearrangement of 7. [e] 7n,o synthesized by DSC activation of amino-
pyridine (see the Supporting Information). [f] Reaction performed with
3.1 equiv Me3SiCl. [g] Attempted rearrangement of 7 returned a com-
plex mixture of products.[43]
The superior performance of the pseudoephedrine-
directed rearrangement in arylations with electron-rich rings
renders this method usefully complementary to other meth-
ods for the arylation of amino acid enolates, which perform
well only with electron-deficient rings.[17–22,34] The only
method currently available for the asymmetric arylation of
amino acids with electron-rich rings requires stoichiometric
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Cr and a large excess of nucleophile.[24] Even related
auxiliary-directed alkylations of amino acids work only with
alanine.[9]
To conclude, the rearrangement of pseudoephedrine-
containing ureas provides a practical method for the asym-
metric arylation of readily available amino acids. The method
uses no heavy-metal catalysts or additives, and is most
successful with electron-rich rings and with amino acids
containing saturated side chains. It proceeds through
a tandem reaction sequence entailing silyl protection, depro-
tonation, rearrangement, auxiliary release, and deprotection,
all taking place in a single operation. The immediate products
are enantioenriched hydantoins that may be converted in high
yield to valuable enantioenriched a-arylated quaternary
amino esters.
The rearrangement returns the pseudoephedrine auxiliary
without the need for a separate hydrolysis step. Recovery of
pseudoephedrine from the product mixture is straightfor-
ward: washing the crude organic fractions from the rearrange-
ment of 9a with 1m HCl takes the pseudoephedrine into the
aqueous layer, from which it can be recovered in 81% yield
(pure by m.p. and [a]D) by basification and extraction.
N-Methylated hydantoins show a range of biological
activities.[44–47] Specifically, hydantoin (R)-9c is the R enan-
tiomer of the anticonvulsant mephenytoin. Our method
provides the first asymmetric synthesis of this compound:
previous approaches used resolution of chiral precursors.[48–50]
Nonetheless, the hydantoins could be straightforwardly and
nearly quantitatively converted to their parent quaternary
amino acids by basic hydrolysis (Scheme 3 shows three
representative examples). The amino acids 13 were conven-
iently isolated as their methyl esters 14 in excellent yield.
The absolute configuration of the products 9 of the
rearrangement was confirmed by comparison with reported
Keywords: amino acids · arylation · chiral auxiliaries · enolates ·
pseudoephedrine
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8961–8965
Angew. Chem. 2015, 127, 9089–9093
[1] A. B. Hughes, Amino Acids, Peptides and Proteins in Organic
Chemistry, Analysis and Function of Amino Acids and Peptides,
Wiley, Hoboken, 2013.
[2] For reviews, see M. I. Calaza, C. Cativiela, Eur. J. Org. Chem.
2008, 3427 – 3448; C. Cativiela, M. D. Díaz-de-Villegas, Tetrahe-
dron: Asymmetry 2007, 18, 569 – 623; H. Vogt, S. Bräse, Org.
Biomol. Chem. 2007, 5, 406 – 430; Y. Ohfune, T. Shinada, Eur. J.
Org. Chem. 2005, 5127 – 5143; C. Cativiela, M. D. Díaz-de-
Villegas, Tetrahedron: Asymmetry 2000, 11, 645 – 732; C. Cati-
viela, M. D. Díaz-de-Villegas, Tetrahedron: Asymmetry 1998, 9,
3517 – 3599.
data. Optical rotation confirmed the configuration of (R)-14a
21
(½aŠ ¼À46.4 (c = 0.5, MeOH, 92:8 e.r.); lit.[51] À51.8, (c = 0.5,
D
MeOH)), and (R)-9c was identical to (R)-mephenytoin
21
(½aŠ ¼À71.4 (c = 0.14, EtOH; 91:9 e.r.); lit.[49] À101.6, (c =
D
0.13, EtOH)). We assume therefore that hydantoins 9 are
formed likewise with R configuration using (S,S)-pseudoe-
phedrine, and with S selectivity using (R,R)-pseudoephe-
drine. The fact that the rearrangements of 3 (Scheme 1) and 7
(Schemes 2 and 3) proceed with opposite stereoselectivity
was confirmed by N methylation of (R)-9a (NaH, MeI, 98%
[3] “Chiral memory” using stereogenic centres: D. Seebach, A. R.
Sting, M. Hoffmann, Angew. Chem. Int. Ed. Engl. 1996, 35,
2708 – 2748; Angew. Chem. 1996, 108, 2881 – 2921.
[4] “Chiral memory” using stereogenic axes (representative exam-
ples): T. Kawabata, T. Wirth, K. Yahiro, H. Suzuki, K. Fuji, J.
Am. Chem. Soc. 1994, 116, 10809 – 10810; T. Kawabata, S.
Kawakami, S. Majumdar, J. Am. Chem. Soc. 2003, 125, 13012 –
13013; T. Kawabata, K. Moriyama, S. Kawakami, K. Tsubaki, J.
Am. Chem. Soc. 2008, 130, 4153 – 4157; M. Branca, S. Pena, R.
Guillot, D. Gori, V. Alezra, C. Kouklovsky, J. Am. Chem. Soc.
2009, 131, 10711 – 10718; M. Branca, D. Gori, R. Guillot, V.
Alezra, C. Kouklovsky, J. Am. Chem. Soc. 2008, 130, 5864 – 5865;
S. P. Fletcher, J. Solà, D. Holt, R. A. Brown, J. Clayden, Beilstein
J. Org. Chem. 2011, 7, 1304 – 1309.
[5] Catalytic functionalisation of enolates (representative exam-
ples): B. M. Trost, K. Dogra, J. Am. Chem. Soc. 2002, 124, 7256 –
7257; P. Fang, M. R. Chaulagain, Z. D. Aron, Org. Lett. 2012, 14,
2130 – 2133; H. Zhou, H. Yang, M. Liu, C. Xia, G. Jiang, Org.
Lett. 2014, 16, 5350 – 5353; J. M. Curto, J. S. Dickstein, S. Berritt,
M. C. Kozlowski, Org. Lett. 2014, 16, 1948 – 1951; B. M. Trost,
L. C. Czabaniuk, J. Am. Chem. Soc. 2012, 134, 5778 – 5781; M.
Weber, W. Frey, R. Peters, Angew. Chem. Int. Ed. 2013, 52,
13223 – 13227; Angew. Chem. 2013, 125, 13465 – 13469; S.
Cabrera, E. Reyes, J. Alemµn, A. Milelli, S. Kobbelgaard,
K. A. Jørgensen, J. Am. Chem. Soc. 2008, 130, 12031 – 12037.
[6] Asymmetric phase transfer reactions: T. Hashimoto, K. Mar-
uoka, Chem. Rev. 2007, 107, 5656 – 5682; D. Uraguchi, Y. Asai, T.
Ooi, Angew. Chem. Int. Ed. 2009, 48, 733 – 737; Angew. Chem.
2009, 121, 747 – 751; T. Kano, T. Kumano, R. Sakamoto, K.
Maruoka, Org. Biomol. Chem. 2013, 11, 271 – 278.
yield), which gave a sample of 6, whose optical rotation
21
D
21
{½aŠ ¼À88.0 (c = 1.0, CHCl3, 88:12 e.r.)} was opposite to that
{½aŠ ¼ + 87.6 (c = 1.1, CHCl3, 12:88 e.r.)} of the compound
D
produced by the reaction shown in Table 1, entry 8.
Given the sense of stereoselectivity of the arylation of 7,
we propose a transition state for rearrangement of 8C related
to those suggested by Myers for alkylations of amino acids.[9]
Typically, tetrasubstituted enolates of related pseudoephe-
drine derivatives form with E geometry. However, to explain
the R selectivity of the rearrangement, we propose the
reaction pathway shown in Scheme 4, in which chelation of
lithium by the electron-rich isourea nitrogen atom during
enolate formation generates the Z enolate 8C. Rotation of
the urea into a reactive conformation then leads to a lower-
face attack on the enolate, providing R-configured prod-
ucts.[52]
[7] Use of auxiliaries: U. Schçllkopf, W. Hartwig, U. Groth, Angew.
Chem. Int. Ed. Engl. 1979, 18, 863 – 864; Angew. Chem. 1979, 91,
922 – 923; R. M. Williams, M. N. Im, J. Am. Chem. Soc. 1991, 113,
9276 – 9286; D. B. Berkowitz, M. K. Smith, J. Org. Chem. 1995,
60, 1233 – 1238; R. Chinchilla, N. Galindo, C. Nµjera, Synthesis
Scheme 4. Stereoselective enolate arylation directed by (S,S)-pseudo-
ephedrine.
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1999, 704 – 717; S. Vassiliou, P. A. Magriotis, Tetrahedron:
Asymmetry 2006, 17, 1754 – 1757.
[8] A. G. Myers, J. L. Gleason, A. T. Yoon, D. W. Kung, J. Am.
Chem. Soc. 1997, 119, 656 – 673.
[34] K. Tomohara, T. Yoshimura, R. Hyakutake, P. Yang, T.
Kawabata, J. Am. Chem. Soc. 2013, 135, 13294 – 13297.
[35] A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, J. Am. Chem.
Soc. 1997, 119, 6496 – 6511.
[9] C. L. Hugelshofer, K. T. Mellem, A. G. Myers, Org. Lett. 2013,
15, 3134 – 3137.
[36] D. A. Kummer, W. J. Chain, M. R. Morales, O. Quiroga, A. G.
Myers, J. Am. Chem. Soc. 2008, 130, 13231 – 13233.
[10] A. Burtoloso, Synlett 2009, 320 – 327.
[11] C. C. C. Johansson, T. J. Colacot, Angew. Chem. Int. Ed. 2010, 49,
676 – 707; Angew. Chem. 2010, 122, 686 – 718.
[37] G.-q. Shi, Q. Wang, M. Schlosser, Tetrahedron 1996, 52, 4403 –
4410; K. Itoh, T. Katsuura, I. Matsuda, Y. Ishii, J. Organomet.
Chem. 1972, 34, 63 – 73; C. Bessenbacher, W. Kaim, T. Stahl,
Chem. Ber. 1989, 122, 933 – 939; M. Paul, E. Frainnet, C. R.
Seances Acad. Sci. Ser. C 1974, 279, 213 – 216.
[38] It is possible that 8A and 8B are unstable toward elimination of
the pseudoephedrine auxiliary, and racemic rearrangement of
some adduct of the resulting ketene takes place in its absence.
[39] M. R. Morales, K. T. Mellem, A. G. Myers, Angew. Chem. Int.
Ed. 2012, 51, 4568 – 4571; Angew. Chem. 2012, 124, 4646 – 4649.
[40] K. T. Mellem, A. G. Myers, Org. Lett. 2013, 15, 5594 – 5597.
[41] The carbamoyl chlorides of 3- and 4-aminopyridine precursors to
7n,o were unstable, and DSC derivatives were used instead (see
the Supporting Information).
[12] O. Gaertzen, S. L. Buchwald, J. Org. Chem. 2002, 67, 465 – 475.
[13] X. Liu, J. F. Hartwig, Org. Lett. 2003, 5, 1915 – 1918.
[14] S. P. Marsden, E. L. Watson, S. A. Raw, Org. Lett. 2008, 10,
2905 – 2908; Y.-X. Jia, J. M. Hillgren, E. L. Watson, S. P. Mars-
den, E. P. Kündig, Chem. Commun. 2008, 4040 – 4042.
[15] K. Li, G. Tan, J. Huang, F. Song, J. You, Angew. Chem. Int. Ed.
2013, 52, 12942 – 12945; Angew. Chem. 2013, 125, 13180 – 13183.
[16] E. Demory, D. Farran, B. Baptiste, P. Y. Chavant, V. Blandin, J.
Org. Chem. 2012, 77, 7901 – 7912.
[17] M. Ma˛kosza, D. Sulikowski, O. Maltsev, Synlett 2008, 1711 –
1713.
[18] V. Lupi, M. Penso, F. Foschi, F. Gassa, V. Mihali, A. Tagliabue,
Chem. Commun. 2009, 5012 – 5014.
[19] F. Foschi, D. Landini, V. Lupi, V. Mihali, M. Penso, T. Pilati, A.
Tagliabue, Chem. Eur. J. 2010, 16, 10667 – 10670.
[20] F. Foschi, A. Tagliabue, V. Mihali, T. Pilati, I. Pecnikaj, M. Penso,
Org. Lett. 2013, 15, 3686 – 3689.
[42] CCDC 1051080 contain the supplementary crystallographic data
for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
[43] By-products were detected, apparently formed through b elimi-
nation of a urea following deprotonation of the benzylic or
allylic b position of 7.
[21] E. P. Jones, P. Jones, A. G. M. Barrett, Org. Lett. 2011, 13, 1012 –
1015.
[44] M. Meusel, M. Gütschow, Org. Prep. Proced. Int. 2009, 36, 391 –
443.
[22] E. P. Jones, P. Jones, A. J. P. White, A. G. M. Barrett, Beilstein J.
Org. Chem. 2011, 7, 1570 – 1576.
[23] S. Shirakawa, K. Yamamoto, T. Tokuda, K. Maruoka, Asian J.
Org. Chem. 2014, 3, 433 – 436.
[24] S. Shirakawa, K. Yamamoto, K. Maruoka, Angew. Chem. Int. Ed.
2015, 54, 838 – 840; Angew. Chem. 2015, 127, 852 – 854.
[25] R. C. Atkinson, D. J. Leonard, J. Maury, D. Castagnolo, N. Volz,
J. Clayden, Chem. Commun. 2013, 49, 9734 – 9736.
[26] J. Clayden, J. Dufour, D. M. Grainger, M. Helliwell, J. Am.
Chem. Soc. 2007, 129, 7488 – 7489.
[45] F. Nique, S. Hebbe, N. Triballeau, C. Peixoto, J.-M. LefranÅois,
H. Jary, L. Alvey, M. Manioc, C. Housseman, H. Klaassen, et al.,
J. Med. Chem. 2012, 55, 8236 – 8247.
[46] K. Last-Barney, W. Davidson, M. Cardozo, L. L. Frye, C. A.
Grygon, J. L. Hopkins, D. D. Jeanfavre, S. Pav, C. Qian, J. M.
Stevenson, et al., J. Am. Chem. Soc. 2001, 123, 5643 – 5650.
[47] E. Ware, Chem. Rev. 1950, 46, 403 – 470.
[48] J. Knabe, W. Wunn, Arch. Pharm. 1980, 313, 538 – 543.
˙
´
[49] H. J. Barton, J. Bojarski, A. Zurowska, Arch. Pharm. 1986, 319,
457 – 461.
[27] J. Clayden, U. Hennecke, Org. Lett. 2008, 10, 3567 – 3570.
[28] D. J. Tetlow, U. Hennecke, J. Raftery, M. J. Waring, D. S. Clarke,
J. Clayden, Org. Lett. 2010, 12, 5442 – 5445.
[29] M. B. Tait, S. Butterworth, J. Clayden, Org. Lett. 2015, 17, 1236 –
1239.
[30] M. B. Tait, P. A. Ottersbach, D. J. Tetlow, J. Clayden, Org.
Process Res. Dev. 2014, 18, 1245 – 1252.
[31] M. A. Vincent, J. Maury, I. H. Hillier, J. Clayden, Eur. J. Org.
Chem. 2015, 953 – 959.
[50] H. Wu, S. Ji, B. Yang, H. Yu, Y. Jin, Y. Ke, X. Liang, J. Sep. Sci.
2012, 35, 351 – 358.
[51] E. Mossel, F. Formaggio, M. Crisma, C. Toniolo, Q. B. Broxter-
man, W. H. J. Boesten, J. Kamphuis, P. J. L. M. Quaedflieg, P.
Temussi, Tetrahedron: Asymmetry 1997, 8, 1305 – 1314.
[52] The different steric requirements of an N-alkylated enolate 4,
which consequently adopts the E geometry observed in Myersꢀ
alkylations, may explain the opposite selectivity noted in the
rearrangement of 3.
[32] D. M. Grainger, A. C. Smith, M. A. Vincent, I. H. Hillier,
A. E. H. Wheatley, J. Clayden, Eur. J. Org. Chem. 2012, 731 –
743.
[33] F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-
VCH, Weinheim, 2013.
Received: March 19, 2015
Revised: May 6, 2015
Published online: June 17, 2015
Angew. Chem. Int. Ed. 2015, 54, 8961 –8965
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8965