Rhodium-catalyzed direct C-H addition of 3,4-dihydroquinazolines to alkenes and their use in the total synthesis of vasicoline

Article abstract of DOI:10.1021/jo052345b

The inter- and intramolecular couplings of unactivated alkenes to 3,4-dihydroquinazolines with a Rh(I) catalyst are reported. Coupling between olefins and NH-3,4-dihydroquinazoline was found to occur consecutively with heterocycle dehydrogenation in the p

Full text of DOI:10.1021/jo052345b

Rhodium-Catalyzed Direct C-H Addition of
3,4-Dihydroquinazolines to Alkenes and Their Use in the Total
Synthesis of Vasicoline
Sean H. Wiedemann,† Jonathan A. Ellman,* and Robert G. Bergman*
Department of Chemistry, UniVersity of California, and DiVision of Chemical Sciences,
Lawrence Berkeley National Laboratory, Berkeley, California 94720
jellman@berkeley.edu; bergman@berkeley.edu
ReceiVed NoVember 12, 2005
The inter- and intramolecular couplings of unactivated alkenes to 3,4-dihydroquinazolines with a Rh(I)
catalyst are reported. Coupling between olefins and NH-3,4-dihydroquinazoline was found to occur
consecutively with heterocycle dehydrogenation in the presence of a Rh(I)/PCy3/HCl catalyst. The reaction
was used to develop an effective method for the synthesis of 2-substituted quinazolines through an oxidative
workup step. The regiocontrolled synthesis and Rh-catalyzed cyclization of alkene-tethered 3,4-
dihydroquinazolines are also described. Applying this method, the second total synthesis of vasicoline
was achieved. The key Rh-catalyzed cyclization step was made possible by the use of a rigid bicyclic
phosphine ligand. The synthesis further demonstrates a challenging Cu-catalyzed amidation of an ortho-
substituted aryl chloride.
Introduction
of electrophilic catalysts for a substrate’s most nucleophilic
position or (2) the complex-induced ortho-directing effect of a
ring-heteroatom. Our group has exploited the latter mechanism
to achieve selective coupling of olefins and aryl iodides to the
2-position of aromatic azoles (Scheme 1).5,6 These reactions are
believed to proceed via a catalyst-substrate complex wherein
Metal-catalyzed C-H activation1 has recently emerged as a
powerful tool for heterocycle functionalization.2 Our group and
others have shown that the C-H activation of N-heterocycles
can be used to achieve coupling to aryl halides3 and addition
across C-C π-bonds.4 The regioselectivity of heterocycle C-H
transformations is generally a result of either (1) the preference
(4) (a) Yi, C. S.; Yun, S. Y.; Guzei, I. A. Organometallics 2004, 23,
5392. (b) Pittard, K. A.; Lee, J. P.; Cundari, T. R.; Gunnoe, T. B.; Petersen,
J. L. Organometallics 2004, 23, 5514. (c) Clement, N. D.; Cavell, K. J.
Angew. Chem., Int. Ed. 2004, 43, 3845. (d) Liu, C.; Han, X.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700. (e) Tan, K. L.;
Tan, K. L.; Park, S.; Ellman, J. A.; Bergman, R. G. J. Org. Chem. 2004,
69, 7329. (f) Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett.
2004, 6, 1685. (g) Tan, K. L.; Vasudevan, A.; Bergman, R. G.; Ellman, J.
A.; Souers, A. J. Org. Lett. 2003, 5, 2131. (h) Ferreira, E. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2003, 125, 9578. (i) Tan, K. L.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2002, 124, 13964. (j) Szewczyk, J. W.; Zuckerman,
R. L.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2001, 40,
216.
† Present address: Graduate School of Pharmaceutical Sciences, University
of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
(1) (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (b)
Jun, C. H.; Lee, J. H. Pure Appl. Chem. 2004, 76, 577. (c) Kakiuchi, F.;
Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(2) (a) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett
2005, 1199. (b) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991.
(3) (a) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew.
Chem., Int. Ed. In press. (b) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 4996. (c) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi,
R.; Viel, S. J. Org. Chem. 2005, 70, 3997. (d) Lewis, J. C.; Wiedemann, S.
H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35. (e) Sezen, B.;
Sames, D. J. Am. Chem. Soc. 2003, 125, 5274. (f) Yokooji, A.; Okazawa,
T.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2003, 59, 5685.
(5) For a summary of this work see: Wiedemann, S. H.; Bergman, R.
G.; Ellman, J. A. In Handbook of C-H Transformations; Dyker, G., Ed.;
Wiley-VCH: Weinheim, Germany, 2005; Vol. 1, p 187.
10.1021/jo052345b CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/04/2006
J. Org. Chem. 2006, 71, 1969-1976
1969

Wiedemann et al.
SCHEME 1
SCHEME 2. Rh-Catalyzed Domino C-H Addition/
Dehydrogenationa
the azole is bound to rhodium as an N-heterocyclic carbene
(NHC) ligand (1).3d,7,8 Just as NHC ligands with either saturated
or aromatic backbones have similar properties,9 we were able
to show that saturated azolines react similarly to aromatic azoles
in the presence of a Rh(I) catalyst.10 For example, 4,4-
dimethyloxazoline can be effectively coupled to unactivated
olefins under mild conditions to give products useful as protected
carboxylic acids.4f
a 5% [Rh] ) 2.5 mol % of [RhCl(coe)2]2, 4 mol % of PCy3‚2HCl, 2.5
mol % of PCy3, THF.
These findings suggest that other heterocycles capable of
forming and stabilizing an NHC tautomer might also be viable
substrates for C-H addition to olefins. The quinazoline skeleton,
in its various oxidation states, is a common structural motif in
compounds that have been isolated and synthesized by medicinal
chemists since the 19th century.11 We now wish to report a new
entry into this compound class via the C-H addition of 3,4-
dihydroquinazolines (DHQs) to olefins. From the inter- and
intramolecular coupling reactions disclosed herein, medicinally
relevant molecular architecture can be assembled. One applica-
tion to the total synthesis of vasicoline is described in detail.
Results and Discussion
Intermolecular Coupling. Parent 3,4-dihydroquinazoline (2)
is a convenient heterocycle synthon because it can be prepared
in one step from commercial starting materials, and it resists
oxidation during prolonged benchtop storage.12 We have previ-
ously reported that 2 can be phenylated at C-2 by iodobenzene
in the presence of a Rh(I) catalyst derived from [RhCl(coe)2]2
and PCy3 (coe ) cis-cyclooctene, Cy ) cyclohexyl).3d This
reaction occurs under conditions identical with those used for
the arylation of azoles, providing evidence for a common
reaction mechanism. As in the arylation reaction, previously
FIGURE 1. Coupling and oxidation of 2 monitored by in situ 1H NMR
analysis.
published conditions for the C-H coupling of azoles to olefins4e
led to the selective alkylation of 2 at the C-2 position (Scheme
2). Unlike the reactions of azoles, however, in the coupling
reaction of 2 with excess 3,3-dimethylbutene a significant
byproduct, aromatized 2-(3,3-dimethylbutyl)-3,4-dihydroquinazo-
line (4, reaction B), was formed in addition to the expected
product, 2-(3,3-dimethylbutyl)quinazoline (3, reaction A).
Given that Rh(I)/PCy3 is a competent catalyst for the transfer
dehydrogenation of alkanes,13 we reasoned that 4 could arise
from formal H2 transfer from 3 to 3,3-dimethylbutene. Other
possibilities include an uncatalyzed dehydrogenation14 of 3 or
initial dehydrogenation of 2 followed by Rh-catalyzed alkylation.
While this latter pathway seems likely given that quinazoline
does indeed couple directly with 3,3-dimethylbutene (reaction
(6) For a thorough study of the C-H activation mechanism operative in
these reactions see: Wiedemann, S. H.; Lewis, J. C.; Ellman, J. A.;
Bergman, R. G. J. Am. Chem. Soc. Accepted for publication.
(7) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 3202.
(8) Cavell and co-workers have disclosed a related, but mechanistically
distinct C-H addition reaction of imidazolium salts to olefins.4c A Ni-
NHC complex analogous to their proposed catalytic intermediates has been
isolated: Clement, N. D.; Cavell, K. J.; Jones, C.; Elsevier, C. J. Angew.
Chem., Int. Ed. 2004, 43, 1277.
1
C), both alternative mechanisms were ruled out by in situ H
NMR analysis (Figure 1).15 During the reaction of 2 with 3,3-
dimethylbutene, quinazoline does not form (reaction D), and
its transient formation along the path to 4 was ruled out because,
in isolated form, quinazoline alkylates more slowly than 2.
(9) (a) Hillier, A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.; Cavallo,
L.; Nolan, S. P. Organometallics 2003, 22, 4322. (b) Lee, M.-T.; Hu, C.-
H. Organometallics 2004, 23, 976.
(10) For a detailed computational study showing insignificant differences
between the oxidative addition reactions of 1,3-dimethylimidazolium and
1,3-dimethyl-4,5-dihydroimidazolium with (PR3)xRhCl, see: Hawkes, K.
J.; McGuinness, D. S.; Cavell, K. J.; Yates, B. F. Dalton Trans. 2004, 2505.
(11) Studies of these alkaloids have been reviewed comprehensively11a
and continue to be reviewed annually.11b (a) Johne, S. In The 2nd
supplements to the 2nd edition of Rodd’s Chemistry of Carbon Compounds;
Sainsbury, M., Ed.; Elsevier: Amsterdam, The Netherlands, 2000; Vol. IV
I/J, pp 203-231. (b) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.
(12) We reported this new synthesis of 2 (ref 3d) based on a previous
2-step synthesis: Burdick, B. A.; Benkovic, P. A.; Benkovic, S. J. J. Am.
Chem. Soc. 1977, 99, 5716-5725.
(13) (a) Wang, K.; Goldman, M. E.; Emge, T. J.; Goldman, A. S. J.
Organomet. Chem. 1996, 518, 55. (b) Itagaki, H.; Murayama, H.; Saito, Y.
Bull. Chem. Soc. Jpn. 1994, 67, 1254.
(14) Spontaneous dehydrogenation of 1,2,3,4-tetrahydroquinazolines has
been described: Telezhenetskaya, M. V.; Plugar, V. N. Khim. Prir. Soedin.
1991, 27, 149. Telezhenetskaya, M. V.; Plugar, V. N. Chem. Nat. Compd.
1991, 27, 133.
(15) The unusual profile observed for the conversion of 2 to 3 cannot
be fully explained at this time.
1970 J. Org. Chem., Vol. 71, No. 5, 2006

Dihydroquinazoline/Olefin Coupling by Rh(I)/PR3
TABLE 1. Rh-Catalyzed Intermolecular C-H Coupling of 2 to
Olefins
Interestingly, complete conversion of 2 to 3 occurs before
any 4 is formed. This result is consistent with the idea that
heterocycles function both as ligands and as substrates during
the olefin coupling reaction. After all DHQ (2) has been
consumed, the catalyst changes its ligand set and is transformed
from a selective C-H coupling catalyst to one that is competent
for transfer hydrogenation.16 With prolonged heating it is
possible to isolate 4 as the major product of the reaction (Scheme
2, reactions A and B). Alternatively, with careful reaction
monitoring, the synthetically useful DHQ product can also be
isolated in good yield (eq 1). DHQs can be readily converted
to the corresponding quinazolines,17 quinazolinones,18 or 1,2,3,4-
tertrahydroquinazolines.19
Despite the moderate yields obtained upon isolation of either
4 or 5, reaction monitoring by in situ 1H NMR analysis revealed
that the coupling of 2 to a variety of monosubstituted olefins
proceeds quantitatively. We therefore sought a convenient
workup protocol that would provide isolated products in yields
more reflective of true coupling efficiency. The best results were
obtained by oxidizing crude coupling reaction mixtures with
MnO2.17 Because MnO2 oxidation converts 2-substituted DHQs
to quinazolines, just as Rh(I)/PR3 does, careful monitoring of
reaction progress is not necessary with this protocol; the
reactions can be terminated anytime after the first equivalent
of olefin is consumed without affecting the yield of isolated
quinazoline products.
a Two steps. b Coupling carried out at 135 °C. c Quantities of all catalyst
components were doubled.
TABLE 2. Regioselective Alkylation of 2
The reaction between various olefins and 2 catalyzed by
[RhCl(coe)2]2, PCy3, and an acid additive20 afforded 2-alkylated
quinazolines in high yield after oxidative workup with MnO2
(Table 1).21 Even olefins susceptible to Rh(I)-catalyzed double-
bond isomerization underwent selective C-C bond formation
at the alkene terminal position (entries 2 and 3). In contrast to
previously reported M-NHC mediated couplings involving
styrene,4e,f 2 was also coupled to styrene in high yield (entry
4). Lower yields were obtained when either the olefin (entry 5)
or the heterocycle (eq 2) was more highly substituted.22
[2,1-b]quinazolines, a common scaffold in medically relevant
natural products. While N-alkylation of 2 provides the most
direct access to alkene-tethered DHQ cyclization substrates,23
no methods for discriminating between the two nucleophilic sites
(N1 and N3) of 2 have been disclosed.24 As resonance arguments
would predict, we found that direct alkylation reactions of 2
run under a variety of conditions afforded regioisomeric
mixtures favoring the conjugated amidine (N3) product. The
combination of polar solvents and low temperatures led to useful
regioselectivities (Table 2).25 When 3-allyl-DHQs were treated
with our typical catalyst mixture derived from [RhCl(coe)2]2
and PCy3‚2HCl26 the expected cyclized products were obtained
in good yields (Table 3).27 The reaction was effectively applied
to a highly substituted olefin (13), selectively affording the
expected cis-fused tetracyclic product. A 1,4-dihydroquinazoline
(15), the minor regioisomer of DHQ alkylation, also underwent
cyclization, albeit with reduced efficiency and selectivity.
Intramolecular Coupling. The intramolecular version of
DHQ/olefin coupling can be used to form ring-fused pyrrolo-
(16) The product of transfer hydrogenation, 2,2-dimethylbutane, was also
detected at levels commensurate with 4 formation.
(17) Kreher, R.; Bergmann, U. Heterocycles 1981, 16, 1693.
(18) Mehta, D. R.; Naravane, J. S.; Desai, R. M. J. Org. Chem. 1963,
28, 445.
(19) Zharekeev, B. K.; Telezhenetskaya, M. V.; Khashimov, K. N.;
Yunusov, S. Y. Khim. Prir. Soedin. 1974, 10, 679. Zharekeev, B. K.;
Telezhenetskaya, M. V.; Khashimov, K. N.; Yunusov, S. Y. Chem. Nat.
Compd. 1974, 10, 704.
(20) The role of the acid additive in accelerating catalysis has not yet
been ascertained.
(21) Excess amounts of olefin (5 equiv with respect to heterocycle) were
used for this work. In previous studies of related reactions, the use of less
than 5 equiv of the olefin component led to significant reductions in reaction
rate4e and yield.4f
(22) In previous studies of related reactions, the coupling of the 1,2-
disubstituted olefin cyclohexene was either ineffective4i or only mildly
effective4f compared to coupling reactions of less substituted olefins.
(23) An elegant, but less convergent method for preparing N3-substituted
DHQs involves selective alkylation of o-aminobenzylamine, using 9-BBN
as a protecting and directing group: Bar-Haim, G.; Kol, M. Tetrahedron
Lett. 1998, 39, 2643.
(24) The sole report of nucleophilic alkylation of 2 (with iodomethane)
claims exclusive N3-selectivity. We were unable to reproduce this result:
Armarego, W. L. J. Chem. Soc. 1961, 2697.
(25) Isomeric mixtures were separated by chromatography.
J. Org. Chem, Vol. 71, No. 5, 2006 1971

Wiedemann et al.
SCHEME 3. General Strategy for the Total Synthesis of
TABLE 3. Rh-Catalyzed Intramolecular Olefin Coupling of
Allyldihydroquinazolines
Vasicoline
none) analogue, vasicolinone.33 Several general strategies for
the synthesis of pyrrolo[2,1-b]quinazolinones have been devel-
oped, including the intramolecular aza-Wittig reaction,34 lactam
condensations with isatoic anhydride,35 and microwave-
promoted cyclodehydrations.36 In contrast, little attention has
been devoted to the synthesis of the more reduced, and
significantly less stable class of alkaloids, the 1,2,3,9-tetrahy-
dropyrrolo[2,1-b]quinazolines, of which vasicoline is a mem-
ber.37
Vasicoline has been synthesized only once previously by
Stevens and Nakagawa.38 Their approach relied on the moder-
ately selective bis-ortho-nitration of 1-benzyl-3-phenylpyrrolid-
2-one by AcONO2. We envisaged forming the B-ring of
vasicoline via the Rh-catalyzed intramolecular olefin coupling
of a suitably functionalized 3-cinnamyl-DHQ (Scheme 3). The
cyclization substrate could be prepared by cinnamylation of 2
with an appropriate alkylating agent.
o-Dimethylaminocimmanyl-3,4-dihydroquinazoline (17) was
chosen as an initial synthetic target because its cyclization would
directly provide vasicoline. Unfortunately, under all reaction
conditions investigated, 17 reacted stoichiometrically, rather than
catalytically, with Rh(I)/PCy3 to give an uncharacterized product
(eq 3). Considering the proximity of the basic dimethyl aniline
a Single isomer. b Quantities of all catalyst components were doubled.
c Not separated.
FIGURE 2. Common alkaloids isolated from Adhatoda Vasica.
Total Synthesis of Vasicoline. Quinazoline natural products
isolated from plant and microbial sources have been studied
for antimalarial,28 antiinflamatory,29 and antitumor30 activity.
Several medicinal herbs of south Asia, such as Adhatoda
Vasica,31 have quinazoline alkaloids as their active constituents
(Figure 2). To demonstrate the utility of our Rh-catalyzed DHQ/
olefin coupling in the preparation of medicinally relevant natural
products, we undertook a total synthesis of one of these
structures, vasicoline.32
Like other quinazoline natural products, vasicoline is typically
isolated together with its 4-oxidized (pyrrolo[2,1-b]quinazoli-
(26) We only recently recognized that the treatment of PCy3 with HCl
in ether at 25 °C can produce both PCy3‚2HCl and PCy3‚HCl. These two
salts perform identically in the applications for which we use them. They
can be independently prepared by using controlled stoichiometry (see
Experimental Section). PCy3‚2HCl is quite hygroscopic and exhibits unusual
spectroscopic properties, especially in the infrared band, on account of its
triple ion, Cl-H-Cl- (bent). For a previous synthesis of phosphonium
dihalohydrogenate salts with neat hydrogen halides at low temperatures
see: Kohle, R.; Kuchen, W.; Peters, W. Z. Anorg. Allg. Chem. 1987, 551,
179.
(27) Interestingly, 12 has been previously synthesized by rhodium-
catalyzed annulation. It was isolated as a byproduct in 20-30% from the
syngas hydroformylation of 2-[(2-methylallylamino)methyl]phenylamine
catalyzed by [Rh(OAc)2]2/PPh3: Campi, E. M.; Habsuda, J.; Jackson, W.
R.; Jonasson, C. A. M.; McCubbin, Q. J. Aust. J. Chem. 1995, 48, 2023.
(28) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett.
1999, 40, 2175.
(29) Al-Shamma, A.; Drake, S.; Flynn, D. L.; Mitscher, L. A.; Park, Y.
H.; Rao, G. S. R.; Simpson, A.; Swayze, J. K.; Veysoglu, T.; Wu, S. T.-S.
J. Nat. Prod. 1981, 44, 745.
(30) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Heterocycles 1997,
46, 541.
(31) (a) Joshi, B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.; Pelletier,
S. W. Tetrahedron: Asymmetry 1996, 7, 25. (b) Amin, A. H.; Mehta, D. R.
Nature 1959, 184, 1317.
moiety of 17 to the site of desired C-C bond formation, catalyst
entrapment may be involved in preventing turnover. We
therefore elected to install the aniline nitrogen atom of vasicoline
at a late stage by metal-catalyzed aryl-chloride amination.39 If
catalyst inactivation by 17 were caused by its ortho substituent,
(33) Vasicolinone has also been twice synthesized in tandem with
rutaecarpine, another structurally homologous quinazolinone alkaloid: (a)
Kaneko, C.; Chiba, T.; Kasai, K.; Miwa, C. Heterocycles 1985, 23, 1385.
(b) Kokosi, J.; Szasz, G.; Hermecz, I. Tetrahedron Lett. 1992, 33, 2995.
(34) (a) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45,
6375. (b) Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y.; Yashima, E.;
Okamoto, Y. J. Org. Chem. 1996, 61, 7316.
(35) Yadav, J. S.; Reddy, B. V. S. Tetrahedron Lett. 2002, 43, 1905.
(36) Liu, J. F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.; Baldino,
C. M.; Wilson, C. J.; Ng, S. C. Org. Lett. 2005, 7, 3363.
(37) Zn0/acetic acid reduction of quinazolinones37a and tandem nitroarene
reduction/condensation strategies37b,c have been used for the synthesis of
1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolines: (a) Karimov, A.; Telezhenet-
skaya, M. V.; Yunusov, S. Y. Khim. Prir. Soedin. 1982, 18, 498. Karimov,
A.; Telezhenetskaya, M. V.; Yunusov, S. Y. Chem. Nat. Compd. 1982, 18,
466. (b) Southwick, P. L.; Cremer, S. E. J. Org. Chem. 1959, 24, 753. (c)
Downes, A. M.; Lions, F. J. Am. Chem. Soc. 1950, 72, 3053.
(32) Johne, S.; Groger, D.; Hesse, M. HelV. Chim. Acta 1971, 54, 826.
(38) Nakagawa, Y.; Stevens, R. V. J. Org. Chem. 1988, 53, 1873.
1972 J. Org. Chem., Vol. 71, No. 5, 2006

Dihydroquinazoline/Olefin Coupling by Rh(I)/PR3
SCHEME 4
SCHEME 5
then presumably cyclization in the presence of a less basic ortho
substituent (e.g. chloride) would be more favorable.
Preparation of a suitable chlorinated cyclization substrate
began from commercially available o-chlorocinnamic acid
(Scheme 4). Esterification followed by hydride reduction
afforded o-chlorocinnamyl alcohol (18) in high yield over two
steps.40 Treatment of 18 with PBr3 gave the corresponding
cinnamyl bromide 19 in high yield, accompanied by minor
amounts of conjugate bromination product 20.41 When 2 was
treated with either pure 19 or a mixture of 19 and 20 in DMF,
cyclization precursor 21 was isolated in good yield after
separation of regioisomers.
We expected 21 to be a challenging substrate for Rh-catalyzed
C-H coupling because similar cinnamyl-substituted hetero-
cycles have cyclized in moderate yield4g and 21, in particular,
has the potential to undergo side reactions arising from Rh-
mediated cleavage of its Ar-Cl bond. Indeed, the conditions
optimized for the cyclization of other N-allyl-3,4-DHQs ([RhCl-
(coe)2]2/PCy3/HCl) provided low turnover and substantial
substrate decomposition when applied to 21. Omitting the acid
additive reduced the amount of undesired de-cinnamylation
products observed. Still, catalyst activity and lifetime were too
low to be synthetically useful.
At this time we became aware of a report describing the use
of conformationally rigid cyclohexyl-Phoban ligands as replace-
ments for PCy3.42 Ruthenium alkylidene catalysts derived from
these ligands exhibit enhanced stability and selectivity for the
self-metathesis of olefins. When 21 was treated with a mixture
of [RhCl(coe)2]2 and one of these ligands (Cy-[3.3.1]-Phoban,43
22), in o-dichlorobenzene, cyclized product 23 was isolated in
good yield (Scheme 5). Alternatively, the catalyst mixture
derived from a more readily available ∼2:1 mixture of Cy-
[3.3.1]-Phoban and exo-Cy-[4.2.1]-Phoban isomers could be
used without reduction in yield.44 Phoban ligands have also
proven to be superior replacements for PCy3 in a related Rh-
(I)-catalyzed C-H activation/arylation of azoles,3a presumably
because they exhibit the steric and electronic properties of bulky
tri-secondary-alkylphosphines while being less susceptible to
cyclometalation-type decomposition.45
Once the carbon framework of vasicoline was in place, we
confronted the challenge of aminating 23. Metal-catalyzed
substitution of an aryl chloride by HNMe2 has not been
previously disclosed, nor did this reaction proceed in our hands
in the presence of various catalysts. In comparison, the metal-
catalyzed substitution of aryl chlorides with ammonia equiva-
lents has been extensively studied. The substitution of 23 with
an ammonia equivalent to give didesmethylvasicoline (24) was
especially attractive to us because 24 is the penultimate
intermediate of Stevens’s vasicoline synthesis. To complete the
formal synthesis of vasicoline we considered a number of aryl
halide amination methods, employing a variety of ammonia
equivalents. Various properties of 23sa relatively unreactive
leaving group (Cl),46 steric hindrance at the position ortho to
the leaving group, and a relatively acidic position R to the
amidinesrendered it a particularly challenging amination
substrate.
Having quickly eliminated Pd-catalyzed carbamate couplings
because they exhibit low reactivity toward aryl chlorides,47 and
catalytic amination methods relying on M[HMDS]x,48 for similar
reasons,49 benzophenone imine emerged as the most appropriate
ammonia synthon for our purposes. It is not sterically demand-
ing, its N-H bond is quite reactive, and it has been shown to
operate in conjunction with mild heterogeneous bases (e.g., K3-
PO4 and CsCO3).50 Despite that, slow hydrodechlorination was
observed as the only reaction between 23 and benzophenone
(45) Hietkamp, S.; Stufkens, D. J.; Vrieze, K. J. Organomet. Chem. 1978,
152, 347.
(46) A synthesis of the -Br analogue of 23 was undertaken starting from
2-bromocinnamic acid. The method used to prepare 23 proved ineffective
in this effort; the Rh-catalyzed cyclization step produced an uncharacterized
(39) We also considered altering our synthetic route by exchanging the
dimethylamino group for an N-protected amino group. These efforts led to
lengthy reaction sequences.
(40) This two-step sequence was preferred to direct reduction of
o-chlorocinnamic acid because common procedures for carboxylic acid
reduction gave competitive conjugate reduction.
(41) Isomerically pure 19 can be obtained by using milder bromination
conditions (e.g., CHBr3/PPh3); however, the PBr3 method is more amenable
to use on large scale.
(42) Forman, G. S.; McConnell, A. E.; Hanton, M. J.; Slawin, A. M. Z.;
Tooze, R. P.; van Rensburg, W. J.; Meyer, W. H.; Dwyer, C.; Kirk, M. M.;
Serfontein, D. W. Organometallics 2004, 23, 4824.
(43) Cy-[3.3.1]-Phoban was prepared in moderate yield by alkylation of
H-[3.3.1]-Phoban with BuLi/CyBr: (a) Meyer, W. H. Personal communica-
tion. (b) Dwyer, C. L.; Kirk, M. M.; Meyer, W. H.; van Rensburg, W. J.;
Forman, G. S. Organometallics. Submitted for publication (om051079p).
(44) Available from radical initiated coupling of CyPH2 with 1,5-
cyclooctadiene (see ref 42).
mixture of decomposition products.
(47) Ar-Cl/carbamate couplings employing Pd/PtBu3
47a
and Pd/
Xantphos47b have been reported: (a) Hartwig, J. F.; Kawatsura, M.; Hauck,
S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5575. (b) Yin, J. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(48) Ar-Cl/M[HMDS]x couplings employing M ) Li48a and Zn48b have
been reported: (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001,
3, 2729. (b) Lee, D. Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
(49) Ortho-Substituted aryl chlorides, normally inactive under Pd/
LiHMDS coupling conditions,48a were shown to be effectively aminated in
the presence of a sterically minimal ammonia shuttle, Ph3SiNH2. Unfor-
tunately, these reaction conditions did not function for 23, probably due to
its base sensitivity: Huang, X. H.; Buchwald, S. L. Org. Lett. 2001, 3,
3417.
J. Org. Chem, Vol. 71, No. 5, 2006 1973

Wiedemann et al.
SCHEME 6
Conclusion
In summary, we have (1) demonstrated that 3,4-dihydro-
quinazolines effectively participate in Rh-catalyzed C-H/olefin
coupling both inter- and intramolecularly, (2) identified an
interesting instance of controlled domino catalysis involving a
Rh-catalyzed dehydrogenation, and (3) utilized DHQ/olefin
couplings to provide access to medicinally relevant substituted
quinazolines and ring-fused dihydroquinazolines via an unusual
bond disconnection. Using Rh-catalyzed C-H activation/olefin
insertion we went on to achieve the second total synthesis of
vasicoline. In the course of our synthesis we demonstrated that
rigid bicyclic trialkylphosphines can function as potent alterna-
tives to PCy3 in C-H activation reactions. Finally, we reported
moderately effective conditions for a particularly challenging
aryl chloride amination using, for the first time, trifluoroaceta-
mide as an ammonia synthon.
imine in the presence of Pd2(dba)3 and Buchwald’s biaryl ligand,
2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl.
Broadening our search of amination methods to include less
conventional approaches, we next considered amide couplings
for the preparation of 24. Amides are not typically used as
ammonia synthons because extreme pH values and temperatures
are required to cleave amide bonds. Nevertheless, based on
Stevens’s use of refluxing HCl as part of a workup procedure
for the synthesis of 24, we were encouraged to consider amide
coupling/amide hydrolysis for the amination of 23. Pd-catalyzed
amide-coupling conditions proved unreactive toward 23,47b even
in the presence of Keay’s potent BINAP-Fu ligand.51 Suc-
cessful C-N bond formation was finally achieved with Buch-
wald’s Cu-catalyzed Goldberg-type amidation method (Scheme
6).52 At elevated temperatures, various aryl and alkyl primary
amides were coupled to 23 in fair yield by a CuI/diamine catalyst
mixture. Trifluoroacetamide was found to give the highest yield
(based on recovered starting material) of aminated product 24
after hydrolytic workup. Changes to catalyst loading, reaction
temperature, and other conditions did not improve conversion
without leading to increased substrate decomposition as well.
The final step in Stevens’ and our synthesis of vasicoline
was the dimethylation of 24. Typical nucleophilic conditions
for this type of transformation were not usable because the
amidine functionality of 24 is more nucleophilic than the NH2
group. Methylation of the anilide anion of 24 was also
ineffective because of competing amidine-enolate formation.
Stevens reported quantitative formation of vasicoline by reduc-
tive amination of formaldehyde with KHFe(CO)4 under CO
atmosphere.53 This very mild reductant was called for because
more typical NaCNBH3-mediated reductive amination condi-
tions led to undesired amidine reduction.54 Although in our
hands Stevens’s published procedure for KHFe(CO)4 reduction
did not lead to high conversion of starting material, by increasing
temperature, pressure, and reagent concentrations we did obtain
vasicoline in 58% yield (Scheme 6). Our synthesis of vasicoline
proceeds in 7 linear steps from commercial materials with 10%
overall yieldsan efficiency identical with that reported for the
Stevens synthesis.
Experimental Section
General Procedure for the Coupling/Oxidation of 2 with
Olefins. In a N2 atmosphere glovebox 2 (132 mg, 1.00 mmol),
[RhCl(coe)2]2 (18 mg, 0.025 mmol), olefin (5 mmol), PCy3‚2HCl
(16 mg, 0.045 mmol), and PCy3 (7 mg, 0.025 mmol) were combined
in 10 mL of a mixture of THF and d8-THF (20:1). An aliquot of
this solution (0.5 mL) was flame sealed under vacuum into a
medium-walled NMR tube. The remainder of the reaction solution
was sealed into a glass-walled vessel equipped with a vacuum
stopcock and both reaction tubes were heated to 150 °C in an oil
bath. Periodically, the NMR tube was removed from the heating
1
bath then cooled to room temperature, and a one-pulse H NMR
1
spectrum was acquired. Once H NMR indicated complete con-
sumption of 2, both reaction vessels were cooled to 25 °C and their
contents transferred to a round-bottom flask with 40 mL of benzene.
MnO2 (1.4 g, 16 mmol) was added to this reaction solution and
then it was heated to reflux for 1 h. While the reaction suspension
was still hot, it was vacuum filtered through Celite. The filter plug
was further rinsed with benzene (25 °C, 10 mL). The filtrate was
concentrated under vacuum and then purified by column chroma-
tography.
General Procedure for the Preparation of 3-Substituted
DHQs. In a round-bottom flask under N2 2 (132 mg, 1.00 mmol)
and alkylating agent (1.10 mmol) were combined in THF (10 mL).
The reaction solution was cooled to -78 °C and a solution of
lithium diisopropylamide (118 mg, 1.10 mmol) in THF (1 mL) was
added dropwise. After 2 h the reaction solution was warmed to 25
°C and stirred overnight. Analysis of the crude reaction mixture
by 1H NMR analysis was used to determine regioselectivity between
3,4-dihydro- and 1,4-dihydroquinazoline products. The crude reac-
tion mixture was concentrated under vacuum onto a small amount
of silica. Column chromatography was used to separate and purify
regioisomers.
General Procedure for Intramolecular Olefin Coupling Reac-
tions of DHQs. In a N2 atmosphere glovebox olefin-tethered DHQ
(1.00 mmol), [RhCl(coe)2]2 (18 mg, 0.025 mmol), PCy3‚2HCl (16
mg, 0.045 mmol), and PCy3 (7.0 mg, 0.025 mmol) were combined
in 10 mL of a mixture of THF and THF-d8 (20:1). An aliquot of
this solution (0.5 mL) was flame sealed under vacuum into a
medium-walled NMR tube. The remainder of the reaction solution
was sealed into a glass-walled vessel equipped with a vacuum
stopcock and both reaction tubes were heated in an oil bath.
Periodically, the NMR tube was removed from the heating bath
then cooled to room temperature, and a one-pulse 1H NMR
spectrum was acquired. After 1H NMR analysis indicated that olefin
had been completely consumed. Both reaction vessels were then
cooled to 25 °C and their contents concentrated under vacuum onto
a small amount of silica. Reaction products were purified by column
chromatography.
(50) (a) Grasa, G. A.; Viciu, M. S.; Huang, J. K.; Nolan, S. P. J. Org.
Chem. 2001, 66, 7729. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.
J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (c) Stauffer, S. R.; Lee,
S. W.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423.
(51) Andersen, N. G.; Parvez, M.; McDonald, R.; Keay, B. A. Can. J.
Chem. 2004, 82, 145.
(52) (a) Klapars, A.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421. (b) Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7727. (c) Ma, D.; Cai, Q.; Zhang, H.
Org. Lett. 2003, 5, 2453.
(53) Watanabe, Y.; Shim, S. C.; Mitsudo, T.; Yamashita, M.; Takegami,
Y. Bull. Chem. Soc. Jpn. 1976, 49, 1378.
(54) We noted equally unselective reduction of 24 when milder NaHB-
(OAc)3 or Eschweiler-Clarke conditions were used.
1974 J. Org. Chem., Vol. 71, No. 5, 2006

Dihydroquinazoline/Olefin Coupling by Rh(I)/PR3
Tricyclohexylphosphonium Hydrogen Dichloride (PCy3‚
2HCl). The reaction was carried out according to a modified
literature procedure that was believed to provide PCy3‚HCl.4g In a
round-bottom flask under N2, PCy3 (1.08 g, 3.85 mmol) was
dissolved in diethyl ether (25 mL). A solution of HCl (1 N in ether,
7.1 mL) was added dropwise with stirring. After 20 min the white
precipitate was filtered under N2 through a glass frit, washed with
ether (2 × 10 mL), and dried under vacuum over P2O5. The resulting
white powder (1.12 g, 82%) was stored under N2. IR (Figure S-2f,
Supporting Information): 2933, 2853, 2393 (P-H), 1451, 765 (vbr,
vs, Cl-H-Cl) cm-1. 1H NMR: δ 7.59 (br s, 1H, ClHCl), 7.22 (br
d, 1H, JP-H ) 482 Hz, PH), 2.54 (m, 3H, PCH), 2.2-1.2 (m, 30H).
13C NMR (100 MHz): δ 28.4 (d, JP-C ) 39.3 Hz), 27.9 (d, JP-C
) 3.4 Hz), 26.3 (d, JP-C ) 12.6), 25.1. 31P NMR (160 MHz): δ
23.0. Anal. Calcd for C18H35Cl2P: C, 61.18; H, 9.98. Found: C,
61.11; H, 10.20.
SO4, filtered, and concentrated under vacuum. The resulting cloudy,
light yellow liquid was distilled (89-91 °C, 0.01 mmHg) (lit. 105-
107 °C, 0.5 mmHg)56 to give 18 as a clear colorless liquid (7.4 g,
1
96%). IR: 3313 (br), 1470, 1440, 1010, 965, 745 cm-1. H NMR
(300 MHz): δ 7.54 (dd, 1H, J ) 7.3, 2.0 Hz), 7.36 (dd, 1H, J )
7.6, 1.7 Hz), 7.20 (m, 2H), 7.01 (d, 1H, J ) 15.9 Hz), 6.35 (dt,
1H, J ) 15.9, 5.6 Hz), 4.37 (dd, 2H, J ) 5.6, 1.4 Hz), 1.62 (br s,
1H). 13C NMR (75 MHz): δ 134.8, 133.1, 131.1, 129.7, 128.7,
127.1, 126.9, 126.8, 63.6. Anal. Calcd for C9H9ClO: C, 64.11; H,
5.38. Found: C, 64.43; H, 5.63.
Mixture of 1-[(E)-3-Bromoprop-1-enyl]-2-chlorobenzene (19)
and 1-(1-Bromoallyl)-2-chlorobenzene (20) (94:6). In a round-
bottom flask 18 (6.0 g, 36 mmol) was dissolved in CCl4 (7 mL)
under N2 and the solution was cooled to 0 °C. PBr3 (3.9 g, 14 mmol)
was added dropwise with stirring over 10 min. The reaction mixture
was stirred for an additional 30 min and then pipetted onto ice
water (40 mL). After an additional 10 min, CH2Cl2 (15 mL) was
added and the resulting organic phase removed. The aqueous phase
was further extracted with CH2Cl2 (20 mL). The combined organic
phases were washed with saturated NaHCO3 (15 mL) then brine
(15 mL), filtered, and concentrated under vacuum. The resulting
light yellow liquid (7.9 g, 96%) was found to contain 19 and 20 in
Tricyclohexylphosphonium Chloride (PCy3‚HCl). In a N2
atmosphere glovebox, PCy3 (500 mg, 1.78 mmol) and diethyl ether
(10 mL) were added to a glass-walled vessel equipped with a
vacuum stopcock. A solution of HCl (1 N in ether, 0.445 mL) was
added dropwise under N2. After being stirred for 2 h the reaction
suspension was filtered and washed with ether (2 × 10 mL) under
N2. The filtrate was concentrated under vacuum to afford unreacted
tricyclohexylphosphine (227 mg, 45%). The filter cake was dried
under vacuum to give PCy3‚HCl as a white powder (268 mg, 48%,
87% based on recovered PCy3). IR (Figure S-2g, Supporting
1
a 94:6 ratio by H NMR analysis. This material was used without
further purification. IR: 1469, 1435, 1200, 1033, 961, 747, 696
cm-1. 19: 1H NMR (300 MHz) δ 7.55 (dd, 1H, J ) 7.3, 2.1 Hz),
7.35 (dd, 1H, J ) 7.3, 2.0 Hz), 7.23 (m, 2H), 7.05 (d, 1H, J )
15.6 Hz), 6.39 (dt, 1H, J ) 15.6, 7.8 Hz), 4.18 (dd, 2H, J ) 7.8,
0.7 Hz). 20: 1H NMR (300 MHz) δ 7.61 (d, 1H, J ) 7.6 Hz), 7.31
(d, 1H, J ) 8.4 Hz), 7.22 (m, 2H), 6.28 (m, 1H), 6.08 (d, 1H, J )
7.5 Hz), 5.35 (d, 1H, J ) 16.7 Hz), 5.24 (d, 1H, 10.0 Hz). 19: 13C
NMR (75 MHz) δ 133.8, 133.3, 130.3, 129.8, 129.3, 127.8, 127.0,
126.9, 32.9. 20: 13C NMR (75 MHz) not detected.
Information): 2935, 2852, 2345 (P-H), 1439, 1299, 931, 884 cm-1
.
1H NMR (400 MHz): δ 8.01 (br d, 1H, JP-H ) 490 Hz, PH), 2.46
(m, 3H, PCH), 2.2-1.2 (m, 30H). 31P NMR (160 MHz): δ 20.6.
Anal. Calcd for C18H34ClP: C, 68.22; H, 10.81. Found: C, 68.17;
H, 11.08.
(E)-3-(2-Chlorophenyl)acrylic Acid Methyl Ester.55 A slurry
prepared from (E)-3-(2-chlorophenyl)acrylic acid (9.1 g, 50 mmol),
concentrated H2SO4 (5.8 g, 59 mmol), and MeOH (100 mL) was
dissolved by heating to reflux (85 °C). Reflux was continued 2 h,
then 80 mL of solvent was removed by distillation (68 °C, 1 atm).
After cooling, 80 mL of fresh MeOH was added and the reaction
was further refluxed overnight. Most of the solvent was removed
by distillation (85 mL, 68 °C, 1 atm) and the remaining cloudy,
biphasic material was treated with ether (100 mL) and ice water
(100 mL). The ether phase was removed, and the aqueous phase
was washed with ether (50 mL). The combined ethereal phases
were washed once with water (50 mL), twice with aqueous Na2-
CO3 (1M, 50 mL), and once with brine (50 mL), then dried over
Na2SO4, filtered, and concentrated under vacuum to give (E)-3-
(2-chlorophenyl)acrylic acid methyl ester as a clear liquid (9.2 g,
94%). IR: 1716, 1635, 1434, 1318, 1171, 758 cm-1. 1H NMR (300
MHz): δ 8.08 (d, 1H, J ) 15.9 Hz), 7.59 (m, 1H), 7.39 (m, 1H),
7.26 (m, 2H), 6.41 (d, 1H, J ) 16.2 Hz), 3.80 (s, 3H). 13C NMR
(125 MHz): δ 166.8, 140.6, 134.9, 132.6, 131.0, 130.1, 127.5,
127.0, 120.4, 51.8. Anal. Calcd for C10H9ClO2: C, 61.08; H, 4.61.
Found: C, 61.14; H, 4.52.
(E)-3-(2-Chlorophenyl)prop-2-en-1-ol (18). In a two-neck
round-bottom flask fitted with an addition funnel and a N2 inlet,
(E)-3-(2-chlorophenyl)acrylic acid methyl ester (9.0 g, 46 mmol)
was dissolved in CH2Cl2 (200 mL). After the reaction solution was
cooled to -78 °C DIBAl-H (1M in toluene, 135 mL) was added
dropwise over 30 min. The reaction mixture was warmed to 0 °C
over 1 h then MeOH (40 mL) was added dropwise, maintaining a
steady rate of gas evolution. The reaction mixture was warmed to
room temperature and stirred for 30 min before adding Rochelle’s
salt (saturated aqueous, 150 mL). The resulting layers were stirred
vigorously until the solution was clear. The organic phase was
removed and the aqueous phase was washed (3 × 150 mL of CH2-
Cl2). The combined organic phases were washed with saturated
Na2SO4 (150 mL) and brine (150 mL) and then dried over Na2-
3-[(E)-3-(2-Chlorophenyl)allyl]-3,4-dihydroquinazoline (21).
In a round-bottom flask, 2 (2.6 g, 20 mmol) was dissolved in DMF
(40 mL) with stirring under N2. After the mixture was cooled to 0
°C, K2CO3 (5.5 g, 40 mmol) and a solution of 19 and 20 (94:6)
(4.6 g, 20 mmol) in DMF (5 mL) were added to the reaction vessel.
The reaction mixture was stirred an additional 1 h at 0 °C and then
overnight at 25 °C. The resulting suspension was then diluted with
THF (120 mL), filtered, and concentrated under vacuum. Analysis
of the crude reaction mixture by 1H NMR indicated a >20:1 ratio
of 3,4-dihydro- to 1,4-dihydroquinazoline products. Column chro-
matography (6:3.5:0.5 f 4.75:4.75:0.5 EtOAc/actone/Et3N) af-
forded 21 (3.7 g, 65%) as a pale yellow powder, which was stored
under nitrogen until use. IR: 1609, 1593, 1569, 1486, 1165, 971,
1
762, 746 cm-1. H NMR (300 MHz): δ 7.52 (m, 1H), 7.37 (m,
1H), 7.27-6.97 (m, 7H), 6.86 (d, 1H, J ) 7.5 Hz), 6.11 (dt, 1H,
1
J ) 15.8, 6.5 Hz), 4.56 (s, 2H), 3.94 (d, 2H, J ) 6.5 Hz). H
NOESY: Figure S-2h, Supporting Information. 13C NMR (75
MHz): δ 149.9, 141.6, 134.1, 133.1, 131.0, 129.8, 129.2, 128.4,
127.0 (2C), 126.1, 125.7, 124.9, 124.6, 120.3, 55.0, 46.5. Anal.
Calcd for C17H15ClN2: C, 72.21; H, 5.35; N, 9.91. Found: C, 72.04;
H, 5.56; N, 9.77.
3-(2-Chlorophenyl)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazo-
line (23). The reaction was carried out according to the general
procedure for intramolecular olefin coupling reactions of DHQs
with 21 (1.13 g, 4.00 mmol), [RhCl(coe)2]2 (143 mg, 0.200 mmol),
and ca. 2:1 mixture of Cy-[3.3.1]-Phoban and exo-Cy-[4.2.1]-
Phoban (135 mg, 0.600 mmol) in 1,2-dichlorobenzene. The reaction
1
tube was heated to 150 °C for 10 h until H NMR indicated that
21 had been completely consumed. Column chromatography eluting
with CH2Cl2 containing 3.3% of a mixture of 15% NH4OH in
MeOH gave 23 as a tan powder (673 mg, 60%), which was stored
under nitrogen until use. If contaminated with trace quinazoline,
23 could be further purified by crystallization (slow vapor diffusion
of hexanes into THF). IR: 1625, 1588, 1568, 1479, 1438, 1167,
1037, 760, 721 cm-1. 1H NMR (300 MHz, C6D6): δ 7.39 (d, 1H,
(55) Terrian, D. L.; Mohammad, T.; Morrison, H. J. Org. Chem. 1995,
60, 1981.
(56) Cignarella, G.; Occelli, E.; Testa, E. J. Med. Chem. 1965, 8, 326.
J. Org. Chem, Vol. 71, No. 5, 2006 1975

Wiedemann et al.
J ) 7.8 Hz), 7.28 (dd, 1H, J ) 7.8, 1.6 Hz), 7.20, (dd, 1H, J )
8.0, 1.2 Hz), 7.05 (t, 1H, J ) 7.6 Hz), 6.94 (d, 1H, J ) 7.4 Hz),
6.88 (d, 1H, J ) 7.6 Hz), 6.75 (td, 1H, J ) 7.7, 1.6 Hz), 6.71 (d,
1H, J ) 7.2 Hz), 4.28 (t, 1H, J ) 8.8 Hz), 4.05 (d, 1H, J ) 13.2
Hz), 3.96 (d, 1H, J ) 13.2 Hz), 2.48 (td, 1H, J ) 8.8, 3.5 Hz),
2.33 (q, 1H, J ) 8.1 Hz), 1.99 (dddd, 1H, J ) 12.7, 9.0, 7.2, 3.5
Hz), 1.46 (dq, 1H, J ) 12.6, 8.1 Hz). 13C NMR (125 MHz): δ
162.8, 143.3, 138.7, 134.0, 129.6, 129.1, 128.4, 128.1, 127.1, 125.7,
124.6, 124.1, 119.3, 49.5, 47.4, 46.1, 28.4. Anal. Calcd for C17H15-
ClN2: C, 72.21; H, 5.35; N, 9.91. Found: C, 72.40; H, 5.40; N,
9.79.
2-(1,2,3,9-Tetrahydropyrrolo[2,1-b]quinazolin-3-yl)phenyl-
amine (24). In a N2 glovebox CuI (84 mg, 0.44 mmol) and (()-
trans-N,N′-dimethylcyclohexane-1,2-diamine (126 mg, 0.88 mmol)
were combined in 1,4-dioxane (5 mL) and stirred at 25 °C until
the CuI completely dissolved. The resulting solution was added to
a glass-walled vessel equipped with a vacuum stopcock containing
23 (500 mg, 1.77 mmol), trifluoroacetamide (400 mg, 3.54 mmol),
and K2CO3 (489 mg, 3.54 mmol). The vessel was then sealed and
heated to 140 °C with stirring for 60 h. After being cooled to 0 °C
the reaction vessel was opened under N2, and HCl (6M, 20 mL)
was added dropwise. The reaction vessel was then resealed and
heated to 75 °C for 9 h. The resulting solution was cooled to 0 °C,
basified with NH4OH, and extracted with ether (40 mL) and CH2-
Cl2 (2 × 40 mL). The combined organic phases were washed with
brine, dried over MgSO4, and concentrated to a brown oil.
Purification by column chromatography using gradient elution with
CH2Cl2 containing 5-10% of a mixture of 10% NH4OH in MeOH
gave 23 (147 mg, 29%) and 24 (171 mg, 37%) as a tan powder.
This material exhibited spectroscopic properties consistent with
literature data.36 1H NMR (400 MHz): δ 7.14-7.08 (m, 2H), 7.05
(td, 1H, J ) 7.6, 1.5 Hz), 6.99-6.92 (m, 2H), 6.87 (d, 1H, J ) 7.1
Hz), 6.78-6.70 (m, 2H), 4.62 (s, 2H), 4.31 (br s, 2H), 4.15 (dd,
1H, J ) 8.6, 5.3 Hz), 3.54 (ddd, 1H, J ) 9.6, 7.3, 7.3 Hz), 3.37
(ddd, 1H, J ) 9.6, 7.8, 4.6 Hz), 2.51-2.34 (m, 2H).
CO for 2 h. Stirring was then ceased to allow the formed white
precipitate (KHCO3) to settle. In a N2 atmosphere glovebox, 825
µL (470 µmol) of the orange KHFe(CO)4 solution was added to a
10 mL steel Parr reactor containing a Teflon stirbar. A suspension
prepared from 24 (50 mg, 190 µmol), formaldehyde (37% aqueous,
77 mg, 950 µmol), and ethanol (1 mL) was also added to the reactor
before it was sealed and pressurized to 5 bar with CO. The reactor
was heated to 105 °C with stirring for 48 h. After cooling to 25 °C
excess CO pressure was released, and the reaction mixture was
treated with 6 M HCl (1 mL). Ethanol was removed under reduced
pressure. The aqueous reaction mixture was then basified with NH4-
OH and extracted with CH2Cl2 (3 × 4 mL). The combined organic
phases were washed with brine, dried over MgSO4, and concentrated
under vacuum. Column chromatography eluting with CH2Cl2
containing 3% of a mixture of 10% NH4OH in MeOH afforded
vasicoline (32 mg, 58%) as a white solid. This material exhibited
spectroscopic properties consistent with literature data.38 Mp 128-
130 °C (lit.32 mp 135 °C). 1H NMR (300 MHz): δ 7.25-6.90 (m,
8H), 4.71 (d, 1H, J ) 13.4 Hz), 4.64 (d, 1H, J ) 13.5 Hz), 4.56
(dd, 1H, J ) 9.2, 7.5 Hz), 3.45-3.30 (m, 2H), 2.72 (s, 6H), 2.56
(dddd, 1H, J ) 12.5, 9.3, 7.7, 4.8 Hz), 1.96 (dtd, 1H, J ) 12.7,
7.8, 7.3 Hz). 13C NMR (75 MHz): δ 165.1, 153.3, 143.6, 137.7,
129.1, 128.4, 127.9, 125.8, 124.7, 124.6, 123.9, 121.0, 119.5, 50.3,
47.7, 46.2, 44.0, 30.0.
Acknowledgment. The authors thank Prof. Brian Keay for
providing the sample of Binap-fu used in this work. Dr.
Wolfgang Meyer of Sasol Corp. is acknowledged for his helpful
advice concerning the synthesis of Cy-[3.3.1]-Phoban. This work
was supported by NIH grant GM069559 (to J.A.E.) and by the
Director and Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U.S. Department of
Energy, under contract DE-AC02-05CH11231 (to R.G.B.).
Supporting Information Available: Procedural details and
analytical data for all new compounds not included in the
Experimental Section and various characteristic spectra mentioned
in Experimental Section. This material is available free of charge
via the Internet at http://pubs.acs.org..
Dimethyl[2-(1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-yl)-
phenyl]amine (Vasicoline). The reaction was run following a
modified literature procedure.38 Under a CO atmosphere, Fe(CO)5
(1.24 g, 6.32 mmol) was dissolved in 100% ethanol (5 mL). To
this solution was added a degassed solution of KOH (1.13 g, 20.1
mmol) in ethanol (6 mL). The resulting solution was stirred under
JO052345B
1976 J. Org. Chem., Vol. 71, No. 5, 2006