α,β-Unsaturated imines via Ru-catalyzed coupling of allylic alcohols and amines

Article abstract of DOI:10.1039/c2ob06921k

A convenient synthesis of α,β-unsaturated imines requiring only an allylic alcohol, an amine and a Ru catalyst has been developed. The use of large excesses of oxidant and the purification of sensitive intermediates can be avoided.

Full text of DOI:10.1039/c2ob06921k

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COMMUNICATION
α,β-Unsaturated imines via Ru-catalyzed coupling of allylic alcohols and
amines†‡
Jared W. Rigoli, Sara A. Moyer, Simon D. Pearce and Jennifer M. Schomaker*
Received 14th November 2011, Accepted 21st December 2011
DOI: 10.1039/c2ob06921k
Milstein group are particularly useful and give quite different
reactivities due to the increased hemi-lability of the diethylamino
ligand of 1d compared to the di-tert-butyl phosphine ligand of
1c. Catalyst 1c gives the imine from primary alcohols and
amines, while 1d yields the same amide product that would be
obtained using catalyst 1b.4b,6
Our interest in utilizing dehydrogenative couplings in the
context of complex molecule synthesis prompted us to examine
more highly functionalized alcohol substrates in these reactions.
For example, treatment of a primary allylic alcohol with a
primary amine could potentially yield six different products
(Table 1, 2a–f) depending on the catalyst (1a–d) employed, as
well as the reaction conditions. The use of allylic alcohols with
A convenient synthesis of α,β-unsaturated imines requiring
only an allylic alcohol, an amine and a Ru catalyst has been
developed. The use of large excesses of oxidant and the
purification of sensitive intermediates can be avoided.
Unsaturated imines are valuable substrates for a number of C–C
and C–N bond formations, including hetero-Diels–Alder, elec-
trocyclization and C–H activation/coupling reactions.1 They are
typically prepared by oxidation of an allylic alcohol to the corre-
sponding α,β-unsaturated aldehyde, followed by immediate con-
densation of the sensitive intermediate with an amine in the
presence of a dehydrating agent.2 Isolated examples of one-pot
conversions of allylic alcohols directly to unsaturated imines
have been reported; however, these methods often require large
excesses of oxidants and dehydrating reagents.3 In this com-
munication, we report a convenient synthesis of α,β-unsaturated
imines that requires only an allylic alcohol, an amine, and a Ru
catalyst. The simplicity of the method allows for the possibility
of direct use of the imine products without the losses typically
associated with the purification of these sensitive compounds.
Catalysts capable of coupling simple alcohols and amines
without prior functionalization represent “green methods” for
preparing esters, ethers, amides, and amines.4–7 These reactions
may proceed via “hydrogen borrowing”, where dehydrogenation
of the substrate is followed by eventual return of the H2 to the
product. For example, catalyst system 1ac (Fig. 1) can yield sec-
ondary amines from primary alcohols and amines using 1,1′-bis
(diphenylphosphino)ferrocene (dppf) as a ligand.7a Oxidative
coupling is also possible if H2 can be eliminated from the reac-
tion mixture. Catalyst 1ab yields amides from the reaction of a
primary alcohol and an amine if a sacrificial hydrogen acceptor
(acetophenone) is used with 1,4-bis(diphenylphosphino)butane
(dppb) as the ligand.4d Catalyst 1b typically forms amides from
primary alcohols and primary or secondary amines.4c The PNP
pincer 1c and the PNN pincer 1d catalysts developed by the
Fig. 1 Common catalysts for coupling alcohols and amines.
Table 1 Catalysts explored for coupling allylic alcohols with amines
entry
catalyst/ligand
resultsa
Department of Chemistry, University of Wisconsin, Madison, 1101
University Ave, Madison, WI 53706, USA. E-mail: schomakerj@chem.
wisc.edu; Fax: +1 608-265-3454; Tel: +1 608-265-2261
†Financial support was provided by start-up funds from the University
of Wisconsin, Madison. The NMR facilities at UW-Madison are funded
by the NSF (CHE-9208463, CHE-9629688) and NIH (RR08389-01).
‡Electronic supplementary information (ESI) available: Experimental
procedures, NMR, and MS data. See DOI: 10.1039/c2ob06921k
1
2
3
4
5
1ab [Ru(p-cymeme)Cl2]2/dppf
1b [Ru(p-cymeme)Cl2]2/iPr2NHC
1ac [Ru(p-cymeme)Cl2]2/dppf
1c (Milstein’s PNP)
21% 2a; 21% 2b
53% 2f
—
50% 2a; 33% 2b
78% 2a
1d (Milstein’s PNN)
a NMR yields using mesitylene as internal standard.
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Table 2 RuPNN-catalyzed coupling of allylic alcohols and amines to unsaturated imines
entry
1
alcohol
amine
product
yielda (conversion) (E : Z)
78% (100%)
2
3a
3a
63% (100%)
3
4
77% (100%)
74% (95%)
3a
3a
5
6
PhNH2 4e
22% (57%)b
4a
72% (100%) (1.8 : 1)
7
8
3b
4c
4a
83% (100%) (2 : 1)
61% (100%) (6 : 1)
9
4a
4a
70% (100%)
10
11
n = 2; 38% (30%)c
n = 1; 15% (51%)c
12
13
4a
4a
46% (85%)
26% (86%)
14
4a
49% (17%)d (95%)
a Standard conditions: 3 M solution of amine (1 mmol) and alcohol (1 mmol) in toluene-d8, 0.2 mmol mesitylene as an internal standard to determine
NMR yields, 1 mol% catalyst, reflux, 24 h under a flow of N2; 100% conversion of the alcohol unless otherwise noted. b The low yield resulted from
incomplete conversion of the substrates. c Exocyclic double bond migrated to give the internal olefin. d Product is the amide.
Ru catalysts also poses several additional challenges; namely,
competing isomerization and further reduction of the unsaturated
imine/amide product.8,9 Indeed, the reaction of 3-methyl-but-2-
enol 3a with benzylamine in the presence of a Ru-dppb based
system 1ab (entry 1, acetophenone as a hydrogen acceptor)
yielded both 2a and a by-product 2b in low yields, instead of the
expected products 2e or 2f.4d
The catalyst system 1b (entry 2) gave the saturated amide 2f,
consistent with the previous reactivity reported for 1b.4c Catalyst
1ac, using dppf as the ligand instead of dppb (entry 3) gave a
complex mixture of unidentified products instead of the expected
2c or 2d.7a Despite the fact that the PNP catalyst (1c, entry 4)
has been reported to yield imines from primary alcohols and
amines, the desired α,β-unsaturated imine 2a was formed in only
50% yield, along with significant amounts of 2b from undesired
reduction of the olefinic double bond. Finally, to our surprise,
Milstein’s PNN catalyst (1d, entry 5) produced 2a as the only
product in 78% yield, with no competing formation of the
expected amides 2e or 2f.
Encouraged by the result obtained using the PNN version of
Milstein’s catalyst 1d, the scope of unsaturated imine formation
was explored using a variety of allylic alcohols and primary
amines (Table 2). The allylic alcohol 3-methyl-but-2-enol 3a,
gave good yields of the α,β-unsaturated imines when electron-
rich primary amines 4a–d were used (entries 1–4). The less
nucleophilic aniline (entry 5) gave lower yields of the unsatu-
rated imine due to slow conversion.4b Geraniol (3b) gave good
yields of the corresponding unsaturated imines (entries 6 and 7),
but significant cis : trans isomerization of the proximal olefin
occurred to yield approximately a 2 : 1 mixture of E and Z
isomers, the same ratio observed when 10 and 11 are prepared
via conventional methods.10 In contrast, when the trisubstituted
allylic alcohol 3c was used, the initial 4 : 1 mixture of E : Z
isomers improved to a 6 : 1 ratio of E : Z isomers (entry 8).
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Table 3 Redox isomerization of secondary allylic alcohols using 1d
(S)-Perillyl alcohol 3d (entry 9) also gave good yields of the
unsaturated imine 13. Importantly, the use of the geraniol and
perillyl alcohol substrates 3b and 3d demonstrated that other
isolated olefins were not prone to reduction under the reaction
conditions.
entry
1
alcohol
product
yield
95%
Ru catalysts are well-known to promote olefin migration.11
Isomerization of the exocyclic double bonds of 3e and 3f to the
internal olefins competed with the formation of the desired unsa-
turated imines 14 and 15 (entries 10–11). The chiral center of 3d
provided us an opportunity to determine if internal olefin
migration could also occur under the reaction conditions. The
absolute configuration of the stereocenter would be inverted if
isomerization occurred, resulting in degradation of the optical
purity of the substrate. However, when 13 was rapidly hydro-
lyzed back to the aldehyde and reduced to 3d, the degradation in
the ee was minimal, indicating that migration of the double bond
was not occurring to any significant extent (see the Supporting
Information for details‡).
2
3
4
89%
80%
trace
5
6
52%
28%
Finally, while trisubstituted allylic alcohols provided high
yields, decreased substitution on the olefin (entries 12–13) led to
lower yields of unsaturated imine products. The decrease in
steric bulk around the olefin gave competing side reactions,
including homocoupling of two molecules of amine to form the
imine.6
The propensity for primary allylic alcohols to yield α,β-un-
saturated imines, rather the amide products typically seen with
catalyst 1d, was initially rather surprising. The increase in
conjugation upon forming the unsaturated imine may drive the
loss of water more readily than in cases involving typical ali-
phatic alcohols; however, we did not explore the mechanism of
the reaction in any detail. Nonetheless, treatment of benzyl
alcohol and benzylamine with 1d (entry 14), a condition that by
inference to previously reported results should give mainly
amide product, gave 49% of the imine and only 17% of the
amide.4b,6
7
73%
a Standard conditions: 3 M solution of amine (1 mmol) and alcohol
(1 mmol) in toluene-d8, 1 mol% catalyst, reflux, 24 h under a flow of
N2; 100% conversion of the alcohol unless otherwise noted.
The reasons for the disparity between the use of 1c (pre-
viously reported to give saturated imines from primary alcohols
and amines) and 1d are not clear to us. Neither catalyst gave the
amide product, but 1c did yield substantial amounts of the satu-
rated imine 2b (Table 1, entry 4). This product could result from
either reduction of the α,β-unsaturated imine with H2 released in
the reaction, or from a Ru-promoted redox isomerization of the
allylic alcohol to the saturated aldehyde, followed by conden-
sation with the amine. Attempts to promote the redox isomeriza-
tion of a primary allylic alcohol in the absence of amine led to
mixtures of products, potentially due to homocoupling of the
alcohol and acetal formation.5 However, secondary allylic alco-
hols (Table 3) did yield ketones under the reaction conditions.8,9
Alkyl and aryl-substituted allylic alcohols 19–21 and 25
smoothly gave the ketone products in good yields (entries 1–3,
7). The propargyl alcohol 22 (entry 4) was not a competent sub-
strate, while the redox isomerization of a bis-allylic alcohol 23
(entry 5) gave predominately the product 23a resulting from iso-
merization at the terminal olefin. The presence of a pyridine
nitrogen slowed the reaction significantly (entry 6), giving only
28% of 24a after 24 h.
Scheme 1 Proposed mechanism for the preparation of α,β-unsaturated
imines from Ru-catalyzed coupling of allylic alcohols and amines.
25 (Scheme 1) can coordinate to the catalyst 1d after deprotona-
tion to give 26. Loss of the hemi-labile NEt2 ligand, followed by
β-hydride elimination would yield an intermediate α,β-unsatu-
rated aldehyde 27 still coordinated to the metal center. At this
point, we envisage two different pathways. First, the unsaturated
aldehyde 28 could be released from the metal by re-coordination
of the NEt2 ligand to give 29, which could lose H2 to regenerate
the active catalyst 1d. Condensation of the unsaturated aldehyde
Although the mechanistic details are unclear at this point, it is
likely that the reaction pathway for primary alcohols follows a
similar one to that proposed by Milstein.4,6 The allylic alcohol
1748 | Org. Biomol. Chem., 2012, 10, 1746–1749
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3 For selected references, see: (a) J. W. Kim, J. He, K. Yamaguchi and
N. Mizuno, Chem. Lett., 2009, 38, 920; (b) H. Sun, F. Su, J. Ni, Y. Cao,
H. He and K. Fan, Angew. Chem., Int. Ed., 2009, 48, 4390; (c) J. S. Foot,
H. Kanno, G. M. P. Giblin and R. J. K. Taylor, Synthesis, 2003, 7, 1055;
(d) L. Blackburn and R. J. K. Taylor, Org. Lett., 2001, 3, 1637;
(e) T. Zweifel, J. Naubron and H. Grutzmacher, Angew. Chem., Int. Ed.,
2009, 48, 559.
4 Examples of the formation of amides from alcohols and amines:
(a) L. U. Nordstrom, H. Vogt and R. Madsen, J. Am. Chem. Soc., 2008,
130, 17672; (b) C. Gunanathan, Y. Ben-David and D. Milstein, Science,
2007, 317, 790; (c) S. Muthaiah, S. C. Ghosh, J. Jee, C. Chen, J. Zhang
and S. H. Hong, J. Org. Chem., 2010, 75, 3002; (d) A. J. A. Watson,
A. C. Maxwell and J. M. J. Williams, Org. Lett., 2009, 11, 2667;
(e) S. Murahashi and T. Naota, Synlett, 1991, 693; (f) S. C. Ghosh,
S. Muthaiah, Y. Zhang, X. Xu and S. H. Hong, Adv. Synth. Catal., 2009,
351, 2643; (g) Y. Zhang, C. Chen, S. C. Ghosh, Y. Li and S. H. Hong,
Organometallics, 2010, 29, 1374; (h) X. Cui, F. Shi, M. K. Tse,
D. Goerdes, K. Thurow, M. Beller and Y. Deng, Adv. Synth. Catal., 2009,
351, 2949.
5 Examples of the formation of esters from alcohols: (a) J. Zhang,
G. Leitus, Y. Ben-David and D. Milstein, J. Am. Chem. Soc., 2005, 127,
10840.
6 Imines from alcohols and amines: B. Gnanaprakasam, J. Zhang and
D. Milstein, Angew. Chem., Int. Ed., 2010, 49, 1468.
7 Examples of the formation of N-alkylated amines from amines and alco-
hols: (a) M. H. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell,
H. C. Maytum, A. J. A. Watson and J. M. J. Williams, J. Am. Chem.
Soc., 2009, 131, 1766; (b) K. Yamaguchi, J. He, T. Oishi and N. Mizuno,
Chem.–Eur. J., 2010, 16, 7199.
28 with an amine would yield the desired unsaturated imine. A
second possibility is attack of the coordinated aldehyde by the
amine to give an intermediate hemiaminal, which could either
undergo β-hydride elimination to give the unsaturated amide (not
observed), or rapidly lose water to yield the imine. Further
mechanistic studies are needed to distinguish between these two
potential pathways and rationalize the differences in reactivity
between 1c and 1d in the coupling of primary allylic alcohols
and amines.
In conclusion, we have demonstrated a mild and atom-econ-
omical approach towards the synthesis of α,β-unsaturated imines
from primary allylic alcohols and amines using a commercially
available ruthenium catalyst. No suprastoichiometric amounts of
oxidants or dehydrating reagents are required. The reaction per-
forms best with trisubstituted allylic alcohols and the reaction
conditions are mild enough to preserve other unsaturated func-
tional groups in the molecule from reduction. The ability of 1d
to catalyze the efficient redox isomerization of secondary allylic
alcohols to the corresponding ketones was also demonstrated for
the first time. Future efforts will focus on utilizing these atom-
economical approaches in complex molecule synthesis and in
convenient tandem reactions.
8 For a review on metal-mediated transposition of allylic alcohols into car-
bonyl compounds, see: R. Uma, C. Crevisy and R. Gree, Chem. Rev.,
2003, 103, 27.
Notes and references
1 For selected references on the uses of unsaturated imines in synthesis,
see: (a) D. A. Colby, R. G. Bergman and J. A. Ellman, J. Am. Chem.
Soc., 2006, 128, 5604; (b) D. A. Colby, R. G. Bergman and J. A. Ellman,
J. Am. Chem. Soc., 2008, 130, 3645; (c) D. F. Maynard and W.
H. Okamura, J. Org. Chem., 1995, 60, 1763; (d) B. Groenendaal,
E. Ruijter and R. V. A. Orru, Chem. Commun., 2008, 5474;
(e) M. Shimizu, I. Hachiya and I. Mizota, Chem. Commun., 2009, 874;
(f) K. M. Oberg and T. Rovis, J. Am. Chem. Soc., 2011, 133, 4785.
2 (a) J. Gawronski, N. Wascinska and J. Gajewy, Chem. Rev., 2008, 108,
5227; (b) J. P. Adams, J. Chem. Soc., Perkin Trans. 1, 2000, 125.
9 For selected references on redox isomerization of allylic alcohols to
ketones and aldehydes, see: (a) B. M. Trost and R. J. Kulawiec, J. Am.
Chem. Soc., 1993, 115, 2027; (b) M. Ito, S. Kitahara and T. Ikariya,
J. Am. Chem. Soc., 2005, 127, 6172; (c) B. M. Trost and R. J. Kulawiec,
Tetrahedron Lett., 1991, 32, 3039.
10 C. Arbones, F. J. Sanchez, M.-P. Marco, F. Camps and A. Messeguer,
Heterocycles, 1990, 31, 67.
11 (a) D. V. McGrath and R. H. Grubbs, Organometallics, 1994, 13, 224;
(b) J. E. Lyons, J. Org. Chem., 1971, 36, 2497; (c) J. K. Stille and
Y. Becker, J. Org. Chem., 1980, 45, 2139.
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