Vanadium-catalyzed addition of propargyl alcohols and imines

Article abstract of DOI:10.1021/ja064011p

A Mannich-type addition of propargylic alcohols and N-methoxycarbonylimines has been achieved by using a vanadium catalyst. The reactivity of the vanadium catalyst could be modulated by modifying the silanol ligands to avoid the background reaction. The s

Full text of DOI:10.1021/ja064011p

Published on Web 07/25/2006
Vanadium-Catalyzed Addition of Propargyl Alcohols and Imines
Barry M. Trost* and Cheol K. Chung
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received June 7, 2006; E-mail: bmtrost@stanford.edu
Scheme 1. Proposed Reaction Mechanism
Simple addition reactions and prototropic rearrangements are two
major types of atom-economical processes.1 More powerful and
useful transformations are possible when these two classes of
reactions are combined. The aldol-type addition reactions of
propargylic alcohols and allenic alcohols recently developed in our
group are good examples of such transformations.2
To extend the scope of the oxovanadium-catalyzed aldol-type
reaction, we considered using imines in a Mannich-type addition
reaction. The inferior reactivity of imines, compared to that of
carbonyl compounds, was an apparent concern we had from the
outset because the simple Meyer-Schuster rearrangement product
may prevail if the nucleophilic addition to the imines is not
efficient.3 Therefore, we began our study by identifying an
appropriate imine substrate for the vanadium catalysis.
rearrangement.4 This is consistent with our own results obtained
in the previous study of the aldehyde addition reaction in which
electron-rich propargyl alcohols provided aldol-type addition
product in higher yield than electron-poor propargyl alcohols.
On the basis of this hypothesis, we synthesized a series of
oxovanadium catalysts bearing electron-withdrawing groups ac-
cording to literature procedures (eq 2).4
The initial screening test results with some readily accessible
imines, such as N-phenyl, N-sulfonyl, N-phosphorylimines, and
O-methyl benzyloxime, were disappointing, producing only the
Meyer-Schuster rearrangement product. This result indicates that,
although the sigmatropic rearrangement was operative, trapping of
the imines was not efficient. Use of the more electrophilic
N-phenylglyoxaldimine resulted in a complex reaction mixture. On
the other hand, the reaction with N-methoxycarbonylimine 3 gave
the desired Mannich addition product 4 in 31% yield along with
an unusual addition product 5 in 57% yield (eq 1).
Curiously, vanadates 1f and 1g with unsymmetrically substituted
arylsilanols failed to give a stable complex. On the other hand, 1b,
1c, and 1d were readily recrystallized and tested in the Mannich-
type addition reaction with the propargylic alcohol 2 and N-
methoxycarbonylimine 3. The results are summarized in Table 1.
The adduct 5 is likely formed by an uncatalyzed background
reaction, as was confirmed by the control experiment run in the
absence of the vanadium catalyst, which provided 5 in quantitative
yield. Remarkably, this aminal adduct 5 was highly stable and did
not revert to 2 and 3 even with prolonged reaction time in the
presence or absence of the vanadium catalyst.
Table 1. Optimization Study
Yield (%)c
entry
catalyst
conditionsa,b
4
5
Encouraged by the somewhat promising result with N-methoxy-
carbonylimine 3, a series of optimization studies was conducted to
minimize the formation of 5, varying parameters such as solvent,
stoichiometry, and additives. While no other attempts were fruitful,
the slow addition of 2 proved beneficial, providing the Mannich
addition product 4 in 54% yield and the simple addition product 5
in 20% yield.
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1b
1c
1d
A
18
54
92
84
79
74
81
53e
74
20
B (20 h)
B (20 h)
B (10 h)
A
B (20 h)d
B (20 h)
B (20 h)
We turned our attention to modifying the vanadium catalyst with
electron-withdrawing groups, which we thought would facilitate
the desired addition reaction pathway by promoting the transes-
terification step (Scheme 1, A f C and E f C). Furthermore, the
placement of electron-withdrawing groups on the vanadium metal
center was expected to increase the Lewis acidity of the catalyst,
thereby accelerating the addition step (D f E) through the activation
of the imines toward electrophilic attack due to enhanced com-
plexation. Indeed, the transesterification was suggested as the rate-
determining step for the oxovanadium-catalyzed Meyer-Schuster
a Catalyst (5 mol %) and 2 (1.2 equiv) were employed. b Method A: A
solution of 2 and 3 and the catalyst in DCE was placed in a reaction vial
and allowed to react at 80 °C for 24 h. Method B: A solution of 2 in DCE
was added slowly over the given time to a solution of 3 and the catalyst at
80 °C, and stirring was continued such that the total reaction time was 24
h. c Isolated yields. d 1b (2.5 mol %) was used. e Meyer-Schuster product
was isolated in 11% yield.
To our delight, all three new catalysts performed well in
suppressing the background reaction compared to the standard
catalyst 1a. Among the vanadium complexes that were examined,
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10.1021/ja064011p CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Rationale for the Z-Selectivity
Table 2. Vanadium-Catalyzed Mannich-type Addition
Attempts to use an enecarbamate as a “masked” imine proved
unsuccessful, providing no reaction.6
To test whether the chirality of starting material was transferred
to the addition product, an enantiomerically enriched propargylic
alcohol 6 was prepared.7 The addition product 7 was obtained in
65% yield, but it showed virtually no enantiomeric excess,
indicating that the vanadium-catalyzed addition occurred in a
nonstereospecific manner under the given conditions (eq 3).8
In summary, the 2-acylallylic carbamates are accessible by an
atom-economic strategy from terminal acetylene, aldehyde, and
N-acylimines by a series of addition reactions by taking advantage
of the ability of oxovanadium complex to induce [3.3] sigmatropic
rearrangement from propargylic alcohols. The optimized conditions
were successfully applied to a range of propargylic alcohols and
aromatic imines. The products of the current reaction, the â-aryl-
substituted Z-enone compounds containing an allylic amino func-
tionality, are not readily accessible with other methods, including
the aza-Baylis-Hillman reaction.9
tris[tri(4-chlorophenyl)silyl]vanadate 1b gave the most desirable
result, providing the Mannich-type addition product 4 in 92% yield
with no noticeable amount of 5. Remarkably, 1b catalyzed the
desired addition reaction even without using the slow addition
procedure (entry 5). In general, better results were obtained with
slower addition of 2 (entries 3-5). The yield eroded when 2.5 mol
% of the catalyst was employed instead of 5 mol % (entry 6). The
vanadium complex 1c showed good performance as well, providing
the addition product in 81% yield, using a slow addition technique
(entry 8). On the other hand, the reaction with the complex 1d was
not as clean as with the other two complexes and produced many
byproducts, including the Meyer-Schuster product in 11% yield
(entry 7).
Adopting the optimized reaction conditions used in entry 3 of
Table 1 as our standard, the variation of the propargylic alcohols
and imines was explored (Table 2).5 All the alcohol substrates
bearing an aryl group at the propargylic position participated well
in the reaction, providing the Mannich-type addition product in good
yield. Unlike the aldehyde addition, the effect of the electronic
character of 2 was not pronounced (entries 5 and 6). Imines with
both electron-donating groups (entries 7 and 8) and electron-
withdrawing groups (entry 9) gave the addition product in moderate
to good yield. Imines containing heteroaromatic groups were also
examined. The imine derived from furfuraldehyde gave the addition
product in somewhat low yield, possibly due to the thermal
instability of the imine (entry 10). On the other hand, the thiophene-
containing imine gave the adduct in high yield (entry 11). The imine
derived from cinnamaldehyde participated moderately well, provid-
ing the 1,2-addition product in 50% yield (entry 12).
Acknowledgment. We thank the National Institutes of Health
(GM13598) for their generous financial support. C.K.C. thanks John
Stauffer Foundation and Eli Lilly & Co. for a graduate fellowship.
Mass spectra were provided by the Mass Spectrometry Facility,
University of San Francisco, supported by the NIH Division of
Research Resources.
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.,
Int. Ed. 1995, 34, 259.
(2) For propargyl alcohol reactions, see: (a) Trost, B. M.; Oi, S. J. Am. Chem.
Soc. 2001, 123, 1230. For allenic alcohol reactions, see: (b) Trost, B.
M.; Jonasson, C.; Wucher, M. J. Am. Chem. Soc. 2001, 123, 12736. (c)
Trost, B. M.; Jonasson, C. Angew. Chem., Int. Ed. 2003, 42, 2063.
(3) (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819. (b) Swaminat,
S.; Narayana, K. V. Chem. ReV. 1971, 71, 429.
(4) Pauling, H.; Andrews, D. A.; Hindley, N. C. HelV. Chim. Acta 1976, 59,
1233.
(5) The imines were prepared according to (a) Kupfer, R.; Meier, S.;
Wurthwein, E. U. Synthesis 1984, 688.
Notably, the addition reaction produced only Z-enones in all
examples. The complete stereoselectivity for the Z-olefin isomer
could be explained by a staggered geometry of the allenoate
structure D (Scheme 2). The approach from the hydrogen-
substituted face (D-b), which leads to Z-enone product F-b, should
be favored over the approach from the aryl-substituted face (D-a)
on steric grounds.
(6) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
2535.
(7) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806.
(8) The nearly complete racemization indicates that the rearrangement may
proceed through an ion-pair intermediate involving a propargylic cation,
instead of a cyclic transition state. For a similar nonstereospecific
oxometal-catalyzed transformation, see: Sherry, B. D.; Radosevich, A.
T.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 6076.
(9) Shi, Y. L.; Xu, Y. M.; Shi, M. AdV. Synth. Catal. 2004, 346, 1220.
The imine derived from pivaldehyde only led to the formation
of the Meyer-Schuster product (44%) and simple adduct (37%).
JA064011P
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