Rapid generation of molecular complexity using "hybrid" multi-component reactions (MCRs): Application to the synthesis of α-amino nitriles and 1,2-diamines

Article abstract of DOI:10.1039/b516192d

Methyleneaziridines can be converted into a wide range of 1,2-diamines and 2-cyanopiperidines in a single operation with the formation of three intermolecular carbon-carbon bonds using a "hybrid" MCR. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b516192d

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COMMUNICATION
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Rapid generation of molecular complexity using ‘‘hybrid’’
multi-component reactions (MCRs): application to the synthesis of
a-amino nitriles and 1,2-diamines{
Jason J. Shiers,a Guy J. Clarkson,a Michael Shipman*a and Jerome F. Hayesb
Received (in Cambridge, UK) 15th November 2005, Accepted 9th December 2005
First published as an Advance Article on the web 6th January 2006
DOI: 10.1039/b516192d
solution,10 or on solid phase.11 It involves ring opening of the
Methyleneaziridines can be converted into a wide range of 1,2-
highly strained aziridine ring at C-3 using a Grignard reagent
under Cu(I) catalysis, and capture of the resultant metalloenamine
with a carbon based electrophile (R2–X). Simple hydrolysis of the
resultant ketimine provides a one-pot method for the synthesis of
1,3-disubstituted propanones (Scheme 1). Considerable variation
in the structure of all three components has been demon-
strated.10,11 Recognising that the methyleneaziridine MCR pro-
ceeds through a ketimine intermediate, we realised that by
amalgamation of the Strecker and methyleneaziridine MCRs, we
could produce a new ‘‘hybrid’’ 4-CR that could generate
considerable molecular complexity in a single vessel (Scheme 1).13
As with any MCR, a major hurdle to be overcome is the
identification of reaction conditions that are compatible with all
the reagents and individual chemical steps. Thus, to achieve the
addition of cyanide to ketimines after ring opening/alkylation, we
needed to find a reagent system that could be used in THF, and at
the same time, could be used to quench excess Grignard reagent
(typically 2 eq. used) from the aziridine ring opening step. After
some optimisation, we established that this could conveniently be
achieved by using a combination of Me3SiCN (1.5 eq.) and acetic
acid (2.5 eq.). Under these conditions, 1-benzyl-2-methyleneaziri-
dine (1) can be converted into the differentially substituted 1,2-
diamines 3–10 in one-pot by way of the corresponding a-amino
nitrile 2 (Scheme 2 and Table 1). In each example, in situ reduction
with LiAlH4 was undertaken because attempts to isolate the highly
hindered a-amino nitriles proved difficult.14 Full experimental
procedures are provided in the Electronic Supporting Information.
diamines and 2-cyanopiperidines in a single operation with the
formation of three intermolecular carbon–carbon bonds using
a ‘‘hybrid’’ MCR.
Multi-component reactions (MCRs) are one-pot processes in
which three or more components come together to form a product
containing substantial elements of all the reactants.1,2 Well-known
examples include the Strecker,3 Passerini,4 Ugi,2a,5 Pauson–
Khand6 and Biginelli7 reactions as well as the Mannich
condensation.8 MCRs provide an inherently more efficient
approach to chemical synthesis than conventional bimolecular
reactions, and as such efforts to develop new MCRs and related
processes continue apace.9 Of course, greater increases in
molecular complexity can be achieved in an MCR when the
number of reaction components is larger. Thus, four-component
reactions (4-CRs) are inherently more powerful than three-
component reactions (3-CRs). Unfortunately, whilst 3-CRs are
quite common (e.g. Mannich, Strecker, Passerini, Pauson–Khand
and Biginelli processes), n-CRs (n ¢ 4) are quite rare. The
enormous interest and widespread use of the Ugi 4-CR stands as
strong testament to the power and utility of such ‘‘higher-order’’
MCRs.2a In this communication, we disclose a new type of 4-CR{
that generates three new intermolecular C–C bonds by the
application of a ‘‘hybrid’’ MCR strategy. Importantly, the
approach developed could be used to transform other existing
n-CRs into more powerful (n + 1)-CRs.
Analysis of existing MCRs reveals that the imine functional
group plays a key role in many of them. Typically, imines are
generated in situ by the condensation of an aldehyde (or ketone)
with an appropriate amine. For example, in the Strecker 3-CR,
a-amino nitrile formation proceeds via nucleophilic addition of
HCN to the corresponding aldimine (or ketimine) (Scheme 1).3
The adducts are readily converted into a-amino acids and related
derivatives, making this reaction of considerable importance
150 years after its discovery. Recently, we reported a new 3-CR
based upon methyleneaziridines,10,11 which are readily made in
two simple steps from the corresponding primary amine and 2,3-
dibromopropene.12 This 3-CR can be performed either in
aDepartment of Chemistry, University of Warwick, Gibbert Hill Road,
Coventry, UK CV4 7AL. E-mail: m.shipman@warwick.ac.uk;
Fax: +44 24765 24429; Tel: +44 24765 23186
bGlaxoSmithKline, Old Powder Mills, Tonbridge, UK TN11 9AN
{ Electronic supplementary information (ESI) available: Full experimental
procedures and compound characterisation data. See DOI: 10.1039/
b516192d
Scheme 1 Rationale behind ‘‘hybrid’’ multi-component reaction.
Chem. Commun., 2006, 649–651 | 649
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Scheme 2 Synthesis of 1,2-diamines 3–10 using MCR.
Table 1 1,2-Diamines 3–10 prepared by MCR
Entry RMgCl
R1–X
Diamine % Yielda
1
2
3
4
5
6
7
8
a
MeMgCl
EtMgCl
BuMgCl
BuMgCl
BuMgCl
iBuMgCl
iBuMgCl
PhCH2Cl
PhCH2Cl
CH2LCHCH2Br
PhCH2Cl
THPOCH2CH2CH2CH2Br 7
3
4
46
41
42
49
34
43
50
47
5
6b
CH2LCHCH2Br
4-MeOC6H4CH2Cl
8
9
10
Fig. 1 ORTEP view of piperidine 13 drawn at 50% probability level.15
PhCH2MgCl 4-MeOC6H4CH2Cl
Yield of isolated product after purification by column
b
the total number of new bonds produced (3 6 C–C; 1 6 C–N;
85%/bond). Encouragingly, using homochiral (S)-14,
chromatography. Structure determined by X-ray crystallography
after conversion to the corresponding cyclic urea (triphosgene, Et3N,
CH2Cl2, 0 uC, 18 h, 69%) (see Electronic Supporting Information).15
>
appreciable levels of asymmetric induction (d.r. 9 : 1) were
observed in the formation of 15 (Scheme 3). The stereochemistry at
C-2 is tentatively assigned as the (S)-configuration in the major
diastereomer.17
In the case of diamine 6, conversion to the corresponding cyclic
urea (triphosgene, Et3N, CH2Cl2, 0 uC, 18 h, 69%) provided
crystals suitable for single crystal X-ray diffraction which enabled
its structure, and hence that of 6, to be unambiguously established
(see Electronic Supporting Information).15 The yields in these
MCRs are quite modest (34–50%), however the efficiency
with respect to each individual C–C bond forming step is good
(¢ 70%/C–C bond). Our preliminary findings suggest its tolerance
with respect to changes in the structure of the methyleneaziridine,
Grignard, and electrophile component are broadly in line with the
simpler ketone MCR.10,11
To conclude, a ‘‘hybrid’’ MCR that combines the essential
features of Strecker and methyleneaziridine MCRs has been
developed that can be used to make a selection of a-amino nitriles
and 1,2-diamines wherein three intermolecular C–C bonds are
produced. In view of the prominent role of the imine functional
group in other MCRs, we believe that this ‘‘hybrid’’ approach
could be used to develop additional ‘‘higher order’’ n-CRs (n ¢ 4).
Work in this direction is ongoing in our laboratories.
This work was supported by the Engineering and Physical
Sciences Research Council and GlaxoSmithKline.
Piperidines can be made by the methyleneaziridine MCR by
using an electrophile bearing two leaving groups in a 1,3-
relationship.10b Treatment of 1 with MeMgCl, 1,3-diiodopropane
then HCN (generated from Me3SiCN and AcOH) provided
piperidine 11 in 55% yield by way of a 4-CR (Scheme 3). The
structure of 11 was unambiguously established by X-ray crystal-
lography of the corresponding primary amide 13 prepared by
hydrolysis of the nitrile substituent (Fig. 1).15,16 Piperidines bearing
different C-2 substituents can be produced by simply changing the
Grignard reagent. For example, 12 was assembled using iBuMgCl
in the MCR. Although the overall yields for these conversions are
again modest, efficiency is very good when viewed in the context of
Notes and references
{ This process involves the reaction of two reagents together to form an
intermediate that is captured by the subsequent addition of further
reagents. Hence it is more precisely defined as a sequential component
reaction, see ref. 2f.
1 For a monograph see: Multicomponent Reactions (Eds.: J. Zhu,
H. Bienayme´), Wiley-VCH, Weinheim, Germany, 2005.
2 For recent reviews, see: (a) A. Domling and I. Ugi, Angew. Chem., Int.
Ed., 2000, 39, 3169; (b) I. Ugi and S. Heck, Comb. Chem. High
Throughput Screening, 2001, 4, 1; (c) L. Weber, Drug Discovery Today,
2002, 7, 143; (d) C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51;
(e) R. V. A. Orru and M. de Greef, Synthesis, 2003, 1471; (f)
D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602; (g)
M. Syamala, Org. Prep. Proced. Int., 2005, 37, 103.
3 A. Strecker, Liebigs Ann. Chem., 1850, 75, 27. For reviews, see: L. Yet,
Angew. Chem., Int. Ed., 2001, 40, 875; Y. Ohfune and T. Shinada, Bull.
Chem. Soc. Jpn., 2003, 76, 1115; H. Groger, Chem. Rev., 2003, 103, 2795
and references therein.
4 M. Passerini, Gazz. Chim. Ital., 1921, 51, 126; M. Passerini and
G. Ragni, Gazz. Chim. Ital., 1931, 61, 964. For recent developments, see:
S. E. Denmark and Y. Fan, J. Am. Chem. Soc., 2003, 125, 7825;
P. R. Andreana, C. C. Liu and S. L. Schreiber, Org. Lett., 2004, 6, 4231
and references therein.
5 I. Ugi, R. Meyr, U. Fetzer and C. Steinbru¨ckner, Angew. Chem., 1959,
71, 386; I. Ugi and C. Steinbru¨ckner, Angew. Chem., 1960, 72,
267.
6 I. U. Khand, G. R. Knox, P. L. Pauson and W. E. Watts, J. Chem. Soc.
D, Chem. Commun., 1971, 36; S. E. Gibson and N. Mainolfi, Angew.
Chem., Int. Ed., 2005, 44, 3022 and references therein.
Scheme 3 One-pot synthesis of 2-cyanopiperidines using MCR.
650 | Chem. Commun., 2006, 649–651
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7 P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360; C. O. Kappe, Tetrahedron,
1993, 49, 6937; C. O. Kappe, Acc. Chem. Res., 2000, 33, 879.
8 C. Mannich and W. Kro¨schl, Arch. Pharm., 1912, 250, 647. For a recent
review, see: A. Co´rdova, Acc. Chem. Res., 2004, 37, 102.
14 a-Amino nitrile 2 readily loses HCN reverting to the ketimine (and
hence ketone). The lability of Strecker products derived from ketimines
has been noted previously, see, for example: P. Vachal and
E. N. Jacobsen, Org. Lett., 2000, 2, 867.
9 For selected recent examples, see: Y. Yamamoto, H. Hayashi,
T. Saigoku and H. Nishiyama, J. Am. Chem. Soc., 2005, 127, 10804;
N. M. Fedou, P. J. Parsons, E. M. E. Viseux and A. J. Whittle,
Org. Lett., 2005, 7, 3179; K. C. Nicolaou, W. J. Tang, P. Dagneau and
R. Faraoni, Angew. Chem., Int. Ed., 2005, 44, 3874; P. G.
Cozzi and E. Rivalta, Angew. Chem., Int. Ed., 2005, 44, 3600;
B. Westermann and S. Dorner, Chem. Commun., 2005, 2116; P. Wipf
and C. R. J. Stephenson, Org. Lett., 2005, 7, 1137; P. A. Wender,
G. G. Gamber, R. D. Hubbard, S. M. Pham and L. Zhang, J. Am.
Chem. Soc., 2005, 127, 2836.
15 Crystal data for 13: C15H22N2O, M = 246.35, colourless block, 0.60 6
0.40 6 0.18 mm, Monoclinic, P2(1)/n (No 14), b = 100.508(8)u, a =
˚
11.149(6), b = 10.559(5), c = 11.588(6) A, T = 180 K , m(Mo-Ka) =
3
0.077 mm21, U = 1341.3(12) A , Z 4, Dcal = 1.220 g cm23, 8760
˚
reflections measured, 3310 unique [Rint = 0.0453], R [I > 2s(I)] = 0.0478,
wR [I > 2s(I)] = 0.1354, GooF = 1.044. CCDC 286808. Crystal data for
the cyclic urea derivative of 6: C23H30N2O, M = 350.49, colourless
block, 0.60 6 0.50 6 0.18 mm, Monoclinic, P2(1)/c (No 14), b =
˚
101.470(13)u, a = 27.33(2), b = 13.742(10), c = 11.347(8) A, T = 180 K ,
m(Mo-Ka) = 0.068 mm21, U = 4176(5) A , Z 8, Dcal = 1.115 g cm23
,
3
˚
10 (a) J. F. Hayes, M. Shipman and H. Twin, Chem. Commun., 2000, 1791;
(b) J. F. Hayes, M. Shipman and H. Twin, Chem. Commun., 2001, 1784;
(c) J. F. Hayes, M. Shipman and H. Twin, J. Org. Chem., 2002, 67, 935;
(d) J. F. Hayes, M. Shipman, A. M. Z. Slawin and H. Twin,
Heterocycles, 2002, 58, 243.
11 J.-F. Margathe, M. Shipman and S. C. Smith, Org. Lett., 2005, 7, 4987.
12 J. J. Shiers, M. Shipman, J. F. Hayes and A. M. Z. Slawin, J. Am.
Chem. Soc., 2004, 126, 6868 and references cited therein.
26328 reflections measured, 10240 unique [Rint = 0.0747], R [I > 2s(I)] =
0.0772, wR [I > 2s(I)] = 0.1880, GooF = 1.012. The asymmetric unit of
the cyclic urea derivative of 6 contains two crystallographically
independent but chemically identical molecules. CCDC 286809. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b516192d.
16 J. N. Moorthy and N. Singhal, J. Org. Chem., 2005, 70,
1926.
13 The concept of combining two or more MCRs to increase the number
of reaction components that can be brought together in a single vessel
has been demonstrated previously. For a remarkable 7-CR based upon
this idea, see: A. Do¨mling and I. Ugi, Angew. Chem., Int. Ed., 1993, 32,
563.
17 This assignment is based on our earlier synthesis of (+)-coniine from
(S)-14 (ref. 10b), wherein hydride was observed to add to the Re face
of the presumed intermediate iminium cation. Assuming cyanide
attack occurs via the same Re face, the (S)-configuration is expected
at C-2.
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